Advertisement
Original Article| Volume 4, ISSUE 2, 100452, February 2023

Overview of Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Targeted Therapy and Supportive Care for Lung Cancer

  • Kaleem Anwar
    Affiliations
    Department of Clinical Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, California

    Department of Pharmacy, University of California Irvine Health, Orange, California
    Search for articles by this author
  • Lee Nguyen
    Affiliations
    Department of Clinical Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, California

    Department of Pharmacy, University of California Irvine Health, Orange, California
    Search for articles by this author
  • Misako Nagasaka
    Affiliations
    Division of Hematology/Oncology, School of Medicine, University of California, Irvine, Irvine, California
    Search for articles by this author
  • Sai-Hong Ignatius Ou
    Affiliations
    Division of Hematology/Oncology, School of Medicine, University of California, Irvine, Irvine, California
    Search for articles by this author
  • Alexandre Chan
    Correspondence
    Corresponding author. Address for correspondence: Alexandre Chan, PharmD, MPH, Department of Clinical Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, California.
    Affiliations
    Department of Clinical Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, California

    Department of Pharmacy, University of California Irvine Health, Orange, California

    Division of Hematology/Oncology, School of Medicine, University of California, Irvine, Irvine, California
    Search for articles by this author
Open AccessPublished:December 17, 2022DOI:https://doi.org/10.1016/j.jtocrr.2022.100452
Overview of Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Targeted Therapy and Supportive Care for Lung Cancer
Previous ArticleSafety and Efficacy Outcomes From a Single-Center Study of Image-Guided Percutaneous Microwave Ablation for Primary and Metastatic Lung Malignancy
Next ArticleTwo Cases of Subsequent Hepatocellular Carcinoma in Immune Checkpoint Inhibitor–Responsive NSCLC: A Case Report

      Abstract

      Introduction

      Oral administration of ritonavir-boosted nirmatrelvir (Paxlovid) was found to be promising in the treatment of coronavirus disease 2019. The active antiviral component nirmatrelvir in Paxlovid is co-formulated with ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor. Many oral targeted therapies indicated for lung cancer are known substrates of CYP 3A4, and concurrent use with Paxlovid may lead to potential drug-drug interaction (DDI). The purpose of this review is to evaluate the potential DDI between targeted therapies and supportive care for lung cancer and ritonavir-boosted nirmatrelvir.

      Methods

      Drug database search in PubMed and the Food and Drug Administration was conducted to identify pharmacokinetic data on oral tyrosine kinase inhibitors (TKIs) used in NSCLC, both Food and Drug Administration approved and those in development. Metabolism pathways for various TKIs are extracted, and the impact of TKI area under the curves and maximum concentration by strong CYP 3A4 inducers and inhibitors is summarized. The most common toxicities and supportive care medications for the TKI were identified.

      Results

      Among EGFR and exon 20 insertion inhibitors, afatinib is least likely to be affected by CYP 3A4, followed by dacomitinib and osimertinib. Among ALK inhibitors, alectinib is the least susceptible to CYP 3A4. ROS1 inhibitors are affected by CYP 3A4 inhibition with the exception of crizotinib. Among MET inhibitors, capmatinib is substantially affected by CYP 3A4 inhibition. Drug exposure of RET inhibitors is expected to increase with CYP 3A4 inhibition, with selpercatinib being the least affected. Certain supportive care medications for lung cancer TKI may have relevant DDIs.

      Conclusions

      The clinical impact of the DDI between lung cancer TKI and ritonavir-boosted nirmatrelvir varies largely on the basis of the susceptibility of CYP 3A4 inhibition caused by the antiviral. Close monitoring and medication adjustments (i.e., dose changes or alternative coronavirus disease 2019 therapy) can be used to overcome DDI to ensure patient safety.

      Keywords

      Introduction

      The Food and Drug Administration (FDA) issued an emergency use authorization for ritonavir-boosted nirmatrelvir (Paxlovid) on December 22, 2021, for the treatment of coronavirus disease 2019 (COVID-19). Nirmatrelvir is an orally bioavailable protease inhibitor that is active against MPRO, a viral protease that plays a vital role in viral replication by cleaving the two viral polyproteins. Currently, nirmatrelvir is administered in tandem with ritonavir, a strong cytochrome P450 (CYP) 3A4 and 2D6 inhibitor, which has been previously used as a pharmacokinetic boosting agent to boost protease inhibitors used to treat human immunodeficiency virus. Coadministration of ritonavir prolongs the serum concentrations of nirmatrelvir to achieve the target therapeutic effect.

      National Institutes of Health. COVID-19 treatment guidelines: ritonavir-boosted nirmatrelvir (paxlovid), https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir%5fpaxlovid-/. Accessed September 2, 2022.

      The current recommended treatment course of ritonavir-boosted nirmatrelvir for COVID-19 is 5 days. Nevertheless, ritonavir-boosted nirmatrelvir comes with substantial drug-drug interactions (DDIs) owing to the ritonavir component of Paxlovid.

      National Institutes of Health. COVID-19 treatment guidelines: ritonavir-boosted nirmatrelvir (paxlovid), https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir%5fpaxlovid-/. Accessed September 2, 2022.

      Hence, it is recommended that providers should carefully review patients’ concomitant medications before prescribing ritonavir-boosted nirmatrelvir to evaluate for any potential DDIs. Ritonavir-boosted nirmatrelvir is contraindicated in patients who have recently (within 2 wk) received a strong CYP 3A4 inducer (such as rifampin or St. John’s wort).
      Food and Drug Administration
      Fact sheet for healthcare providers. Emergency use authorization for paxlovid.
      https://www.fda.gov/media/155050/download
      Date accessed: September 2, 2022
      Recent advances with the management of lung cancer have led to approval of a number of targeted therapies, which improves the prognosis and survival for a number of lung cancer subtypes. Among these targeted therapies are tyrosine kinase inhibitors (TKIs). TKIs are a group of medications that disrupt the downstream signal transduction pathways of protein kinases by various modes of inhibition.

      Thomson RJ, Moshirfar M, Ronquillo Y. Tyrosine kinase inhibitors. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. https://www.ncbi.nlm.nih.gov/books/NBK563322/?report=classic. Accessed September 2, 2022.

      TKI target-specific enzymes (e.g., EGFR, HER2, ALK, MET, BCR-ABL) are categorized as receptor tyrosine kinases, nonreceptor tyrosine kinases, or dual-specificity kinases. TKIs are indicated for treatment of various malignancies, from solid tumors, such as in breast cancer and NSCLC, to acute myelogenous leukemia. Furthermore, many of these targeted agents are orally available, which brings convenience to patients as they can conveniently receive this treatment in the outpatient setting. Unfortunately, many of these agents are also subjected to DDIs owing to their drug profile.

      NCCN. Non-small cell lung cancer, Version 4. 2022. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed September 3, 2022.

      This has raised concerns about the safe use of ritonavir-boosted nirmatrelvir for COVID-19 infections in patients receiving concomitant oral TKI. The coadministration of these agents will increase the risk for severe toxicities associated with TKI (e.g., interstitial lung disease, pneumonitis, hepatotoxicity, QTc prolongation) owing to the pharmacokinetic-enhancing effects of ritonavir and the narrow therapeutic window of TKI. Another concern is the potential impact of oral TKI on ritonavir-boosted nirmatrelvir, which may alter the efficacy for treating the viral infection and safety of the medication. Therefore, the purpose of this review is to evaluate known pharmacokinetic profiles of common and emerging TKIs so that clinicians can make safe recommendations regarding the coadministration of ritonavir-boosted nirmatrelvir and TKI.

      Materials and Methods

      A search was conducted to identify oral TKIs that are used in NSCLC in August 2022, which were approved by the FDA, used in clinical practice for lung cancer on the basis of expert opinion, and those in development. A comprehensive search of FDA package inserts was conducted using the FDA drug database. For those TKIs in which FDA package inserts were not available, a literature search using PubMed was conducted to identify pharmacokinetic data. The search was conducted using brand, generic, and clinical trial-coded names of identified TKIs (e.g., gefitinib, erlotinib, afatinib, osimertinib, aumolertinib, furmonertinib, alectinib, brigatinib, lorlatinib, crizotinib, entrectinib, repotrectinib, taletrectinib, capmatinib, tepotinib, selpercatinib, pralsetinib, sotorasib, adagrasib, tucatinib, larotrectinib, cabozantinib, mobocertinib, dabrafenib, trametinib, MRTX849). The search was limited to English-language articles published between 2000 and August 2022. A manual search of clinical trial protocols was conducted for drugs in development and not currently approved by the FDA to identify the necessary information. Last, toxicities related to TKI were identified through package inserts, and the list of toxicities was cross-referenced with current National Comprehensive Cancer Network guidelines on supportive care.
      Once oral TKIs and supportive care medications were identified, FDA package insert data for metabolism, excretion, pharmacokinetic induction, and inhibition were extracted (Supplementary Appendix). Data on the change of TKI area under the curve (AUC) and Cmax on the basis of strong CYP 3A4 inducer (rifampin) and strong CYP 3A4 inhibitor (ketoconazole, itraconazole, or posaconazole) were also extracted. For those TKIs with no FDA package inserts, a search was conducted to identify international package inserts, primary literature, and protocols. Collected data were then consolidated to determine the impact of ritonavir-boosted nirmatrelvir on lung cancer TKIs and supportive care medications, including TKIs on ritonavir-boosted nirmatrelvir. Because no patients were included in this study, no consent was required.

      Results

      Impact of Lung Cancer TKI on Ritonavir-Boosted Nirmatrelvir

      Because ritonavir-boosted nirmatrelvir is a substrate of CYP 3A4, induction or inhibition of CYP 3A4 by oral TKI can lead to a decreased or increased concentration of ritonavir-boosted nirmatrelvir. In fact, induction of ritonavir-boosted nirmatrelvir may potentially decrease its efficacy, and the concomitant use of strong CYP 3A4 inducers is contraindicated according to the emergency use authorization of the FDA. Conversely, inhibition of ritonavir-boosted nirmatrelvir can increase concentrations of the medication leading to increased risk of adverse effects (e.g., dysgeusia, diarrhea, hypertension, and myalgia) (Table 1).
      Table 1Metabolism Profiles of Lung Cancer TKIs
      TKIs% of Dose Recovered (% Recovered Unchanged)Metabolism
      FecesUrineMajor SubstrateMinor SubstrateInducesInhibits
      EGFR inhibitors
      Gefitinib
      Food and Drug Administration
      IRESSA (gefitinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206995s003lbl.pdf
      Date accessed: September 2, 2022
      		86<4CYP3A4CYP2D6CYP2C19, CYP2D6
      Erlotinib
      Food and Drug Administration
      TARCEVA® (erlotinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf
      Date accessed: September 2, 2022
      		83 (1)8 (0.3)CYP3A4CYP1A2, CYP1A1
      Afatinib
      Food and Drug Administration
      GILOTRIF® (afatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf
      Date accessed: September 2, 2022
      		85 (74.8)4 (3.52)<2% Metabolized by FMO3, otherwise negligible
      Osimertinib
      Food and Drug Administration
      TAGRISSO™ (osimertinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf
      Date accessed: September 2, 2022
      		6814CYP3A4CYP3A4 (pregnane X dependent), CYP1A2CYP3A4
      AumolertinibUnknownUnknownCYP3A4
      Furmonertinib
      • Zou H.X.
      • Zhang Y.F.
      • Zhong D.F.
      • et al.
      Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model.
      Acta Pharmacol Sin. 2022; 43: 1865-1874
      		71.26.63CYP3A4CYP3A4
      Icotinib
      • Liu D.
      • Jiang J.
      • Zhang L.
      • et al.
      Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects.
      Cancer Chemother Pharmacol. 2014; 73: 721-727
      ,
      • Zhang T.
      • Zhang K.
      • Ma L.
      • et al.
      Metabolic pathway of icotinib in vitro: the differential roles of CYP3A4, CYP3A5, and CYP1A2 on potential pharmacokinetic drug-drug interaction.
      J Pharm Sci. 2018; 107: 979-983
      		CYP3A4

      CYP2C19      		CYP3A5

      CYP1A2
      Dacomitinib

      Food and Drug Administration. VIZIMPRO® (dacomitinib) FDA package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf. Accessed

      		79 (20)3 (<1)CYP2D6CYP3A4
      Lazertinib
      Food and Drug Administration
      Lazertinib Korean package insert.
      https://nedrug.mfds.go.kr/pbp/CCBBB01/getItemDetail?itemSeq=202100467
      Date accessed: September 2, 2022
      		24 (unknown)4.4 (unknown)CYP3A4CYP3A4
      EGFR exon 20 insertion
      Mobocertinib
      Food and Drug Administration
      EXKIVITY™ (mobocertinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215310s000lbl.pdf
      Date accessed: September 2, 2022
      		76 (6)4 (1)CYP3ACYP3A
      Sunvozertinib

      ClinicalTrials.gov. A phase I/II, open-label, multicenter student to assess the safety, tolerability, pharmacokinetics and anti-tumor efficacy of DZD9008 (Sunvozertinib) in patients with advanced non-small cell lung cancer (NSCLC) with EGFR or HER2 mutation. https://clinicaltrials.gov/ct2/show/NCT03974022. Accessed September 2, 2022.

      (DZD9008)      		Unspecified but largely feces and biliary routeCYP3A4

      CYP3A5      		CYP3A4
      ALK inhibitors
      Alectinib
      Food and Drug Administration
      ALECENSA® (alectinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208434s003lbl.pdf
      Date accessed: September 2, 2022
      		98 (84)<0.5CYP3A4
      Brigatinib
      Food and Drug Administration
      ALUNBRIG® (brigatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208772s008lbl.pdf
      Date accessed: September 2, 2022
      		65 (26.65)25 (21.5)CYP3A4

      CYP2C8      		CYP3A4
      Lorlatinib

      Food and Drug Administration. LORBRENA® (lorlatinib) FDA package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210868s004lbl.pdf. Accessed 02 September 2, 2022.

      		41 (9)48 (<1)CYP3A4CYP2C8, CYP2C19, CYP3A5CYP3A

      CYP2B6

      CYP2C9
      ROS1 inhibitors
      Crizotinib
      Food and Drug Administration
      XALKORI® (crizotinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202570s030lbl.pdf
      Date accessed: September 2, 2022
      		63 (53)22 (2.3)CYP3ACYP3A, CYP2B6
      Entrectinib
      Food and Drug Administration
      ROZLYTREK (entrectinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf
      Date accessed: September 2, 2022
      		83 (36)3CYP3A4CYP3A4
      Repotrectinib
      Cleveland Clinic
      A phase 1/2. open-label, multi-center, first-in-human study of the safety, of the safety, tolerability, pharmacokinetics, and anti-tumor activity of TPX-0005 , of TPX-0005 (repotrectinib) in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1–3 rearrangements (TRIDENT-1).
      https://my.clevelandclinic.org/clinical-trials/1251-a-phase-12-open-label-multi-center-first-in-human-study-of-the-safety-tolerability-pharmacokinetics-and-anti-tumor-activity-of-tpx-0005-in-patients-with-advanced-solid-tumors-harboring-alk-ros1-or-ntrk1-3-rearrangements-trident-1
      Date accessed: September 2, 2022
      		UnknownUnknownCYP3A4CYP3A4

      CYP2B6      		CYP2C8/9

      CYP2C19

      CYP3A4
      Taletrectinib

      Cleveland Clinic. A single-arm, open-label, multicenter phase 2 study to evaluate the efficacy and safety of taletrectinib in patients with advanced or metastatic ROS1 positive NSCLC and other solid tumors. https://my.clevelandclinic.org/clinical-trials/1558-a-single-arm-open-label-multicenter-phase-2-study-to-evaluate-the-efficacy-and-safety-of-taletrectinib-in-patients-with-advanced-or-metastatic-ros1-positive-nsclc-and-other-solid-tumors. Accessed September 2, 2022.

      		UnknownUnknownCYP3A4

      CYP3A5
      MET inhibitors
      Capmatinib
      Food and Drug Administration
      TABRECTATM (capmatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213591s000lbl.pdf
      Date accessed: September 2, 2022
      		78 (42)22 (negligible)CYP3A4CYP1A2
      Tepotinib
      Food and Drug Administration
      TEPMETKO® (tepotinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214096s000lbl.pdf
      Date accessed: September 2, 2022
      		85 (45)13.6 (7)CYP3A4

      CYP2C8
      RET inhibitors
      Selpercatinib
      Food and Drug Administration
      RETEVMOTM (selpercatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf
      Date accessed: September 2, 2022
      		69 (14)24 (12)CYP3A4CYP3A, CYP2C8
      Pralsetinib
      Food and Drug Administration
      GAVRETO™ (pralsetinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214701s000lbl.pdf
      Date accessed: September 2, 2022
      		73 (66)6 (4.8)CYP3A4CYP2D6, CYP1A2CYP3A4,

      CYP3A5,

      CYP2C8,

      CYP2C9      		CYP3A4, CYP3A5, CYP2C8,

      CYP2C9
      KRAS p.G12C mutations
      Sotorasib
      Food and Drug Administration
      LUMAKRAS™ (sotorasib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214665s000lbl.pdf
      Date accessed: September 2, 2022
      		74 (53)6 (1)CYP3ACYP2C8,

      CYP2C9,

      CYP2B6
      Adagrasib40.3 (predominately unchanged)0.036 (predominately unchanged)CYP3A4CYP3A4CYP2B6,

      CYP2C9,

      CYP3A4,

      CYP2D6
      HER2 ± HER4 inhibitors
      Tucatinib
      Food and Drug Administration
      TUKYSATM (tucatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213411s000lbl.pdf
      Date accessed: September 2, 2022
      		86 (16)4.1 (NA)CYP2C8CYP3ACYP3A, CYP2C8
      Neratinib
      Food and Drug Administration
      NERLYNX (neratinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208051s000lbl.pdf
      Date accessed: September 2, 2022
      		91.11.13CYP3A4
      NTRK inhibitor
      Larotrectinib
      Food and Drug Administration
      VITRAKVI® (larotrectinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/211710s004lbl.pdf
      Date accessed: September 2, 2022
      		58 (5)39 (20)CYP3A4CYP3A4
      MEK/BRAF inhibitors
      Dabrafenib
      Food and Drug Administration
      TAFINLAR® (dabrafenib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s010lbl.pdf
      Date accessed: September 2, 2022
      		71 (NA)23 (NA)CYP2C8

      CYP3A4      		CYP3A4,

      CYP2C9,

      CYP1A2,

      CYP2B
      Trametinib
      Food and Drug Administration
      MEKINIST® (trametinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s007lbl.pdf
      Date accessed: September 2, 2022
      		80 (<0.1)20 (0.1)CYP2C8
      Cobimetinib
      Food and Drug Administration
      COTELLIC (cobimetinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf
      Date accessed: September 2, 2022
      		76 (6.6)17.8 (1.6)CYP3ACYP3A, CYP2D6
      Vemurafenib
      Food and Drug Administration
      ZELBORAF® (vemurafenib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429s012lbl.pdf
      Date accessed: September 2, 2022
      		94 (NA)1 (NA)CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5
      Encorafenib
      Food and Drug Administration
      BRAFTOVI™ (encorafenib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf
      Date accessed: September 2, 2022
      		47 (5)47 (2)CYP3A4CYP2C19CYP2B6

      CYP2C9

      CYP3A4      		CYP2B6,

      CYP2C8/9,

      CYP2D6

      CYP3A4
      Binimetinib
      Food and Drug Administration
      MEKTOVI® (binimetinib) package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf
      Date accessed: October 1, 2022
      		62 (32)31 (6.5)CYP1A2

      CYP2C19
      Multiple-target TKIs
      Cabozantinib
      Food and Drug Administration
      CABOMETYX® (cabozantinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208692s003lbl.pdf
      Date accessed: September 2, 2022
      		54 (43)27 (not detectable)CYP3A4CYP1A1CYP2C8
      Anlotinib
      • Sun Y.
      • Niu W.
      • Du F.
      • et al.
      Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors.
      J Hematol Oncol. 2016; 9: 105
      ,
      • Zhong C.C.
      • Chen F.
      • Yang J.L.
      • et al.
      Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species.
      Acta Pharmacol Sin. 2018; 39: 1048-1063
      		2.2 (NA)0.9 (NA)CYP3A4

      CYP3A5      		CYP3A4

      CYP2C9
      NA, not applicable; TKI, tyrosine kinase inhibitor.

      EGFR Inhibitors (Gefitinib, Erlotinib, Afatinib, Osimertinib, Aumolertinib, Furmonertinib, Icotinib, Dacomitinib, Lazertinib)

      Oral TKIs that target EGFR typically are not inhibitors or inducers of CYP enzymes, apart from gefitinib, osimertinib, furmonertinib, sunvozertinib, and lazertinib. Gefitinib is an inhibitor of CYP 2C19 and 2D6, which can increase the concentration of ritonavir-boosted nirmatrelvir given that ritonavir is a minor substrate of CYP 2D6. Osimertinib is both an inducer and an inhibitor of CYP 3A4, though induction is dependent on the activation of pregnane X receptor. The CYP induction caused by osimertinib is minimal and likely will not result in substantial changes in the efficacy of ritonavir-boosted nirmatrelvir. Besides osimertinib, lazertinib is the only other EGFR inhibitor that inhibits CYP 3A4. Furmonertinib and sunvozertinib are inducers of CYP 3A4; however, the strength of induction is not well understood at this time.

      EGFR Exon 20 Insertion (Mobocertinib, Sunvozertinib)

      Mobocertinib is a weak inducer and sunvozertinib is an inducer of CYP 3A4, which may lead to decreased concentrations of ritonavir-boosted nirmatrelvir. Currently, it is unknown whether reductions in concentration are clinically relevant.

      HER2 ± HER4 Inhibitors (Tucatinib, Neratinib)

      Tucatinib is a strong inhibitor of CYP 3A4 and will increase concentrations of ritonavir-boosted nirmatrelvir, which increases the risk of its adverse effects. Neratinib is not an inhibitor or an inducer and is not expected to alter metabolism of ritonavir-boosted nirmatrelvir.

      ALK Inhibitors (Alectinib, Brigatinib, Lorlatinib)

      Alectinib and brigatinib are neither inhibitors nor inducers of CYP 3A4. Lorlatinib is an inducer of CYP 3A4 and may reduce exposure of ritonavir-boosted nirmatrelvir.

      ROS1 Inhibitors (Crizotinib, Entrectinib, Repotrectinib, Taletrectinib)

      Crizotinib, entrectinib, and repotrectinib are inhibitors of CYP 3A4 which may lead to increased concentrations of ritonavir-boosted nirmatrelvir and the associated adverse effects. Taletrectinib is neither an inducer nor an inhibitor of CYP 3A4. ROS1 inhibitors are not known to be inducers of CYP 3A4.

      MET Inhibitors (Capmatinib, Tepotinib)

      Capmatinib and tepotinib are not inducers of inhibitors of CYP 3A4.

      RET Inhibitors (Selpercatinib, Pralsetinib)

      Both selpercatinib and pralsetinib are inhibitors of CYP 3A which can lead to increased concentrations of ritonavir-boosted nirmatrelvir, increasing the potential for adverse effects. Because pralsetinib is a weak inducer of CYP 3A4, the concentrations of ritonavir-boosted nirmatrelvir may be decreased; however, the clinical relevance is currently unknown.

      MEK/BRAF Inhibitors (Dabrafenib, Trametinib, Cobimetinib/Vemurafenib, Encorafenib/Binimetinib)

      Cobimetinib, vemurafenib, and encorafenib are all inhibitors of CYP 3A4, which can lead to increased concentrations of ritonavir-boosted nirmatrelvir, increasing the potential for adverse effects. Encorafenib and dabrafenib are inducers of CYP 3A4, which may lead to decreased concentrations of ritonavir-boosted nirmatrelvir, but the clinical impact of these interactions is currently unknown. Trametinib is not an inducer or inhibitor of CYP 3A4; thus, it is unlikely to cause any changes to ritonavir-boosted nirmatrelvir.

      NTRK Inhibitor (Larotrectinib)

      Larotrectinib is an inhibitor of CYP 3A4, which can result in increased concentrations of ritonavir-boosted nirmatrelvir and its adverse effects when taken concomitantly.

      KRAS p.G12C Mutations (Sotorasib, Adagrasib)

      Sotorasib is not an inducer or an inhibitor of CYP 3A4 and is unlikely to affect concentrations of ritonavir-boosted nirmatrelvir. Adagrasib, however, induces and inhibits CYP 3A4 enzymes. The clinical relevance of this interaction on ritonavir-boosted nirmatrelvir is currently unknown.

      Multiple-Target TKIs (Cabozantinib, Anlotinib)

      Anlotinib is an inhibitor of CYP 3A4 which can result in increased concentrations of ritonavir-boosted nirmatrelvir and its adverse effects when taken concomitantly. Cabozantinib is not known as an inhibitor or inducer of CYP 3A4.

      Impact of Ritonavir-Boosted Nirmatrelvir on Lung Cancer TKI

      Ritonavir-boosted nirmatrelvir is a strong inhibitor of CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A (Table 2). Currently, it is contraindicated to be co-administered with drugs that are highly dependent on CYP3A for clearance. In this section, we will review the interaction potential of ritonavir-boosted nirmatrelvir on various TKIs. Dose-attenuation information from manufacturers is summarized in Table 3.
      Table 2CYP3A4 Enzyme Interaction With Various TKIs
      TKIsChange of TKI AUC and Cmax
      Rifampin (Strong CYP3A4 Inducer)Ketoconazole/Itraconazole/Posaconazole (Strong CYP3A4 Inhibition)
      EGFR inhibitors
      Gefitinib↓ AUC 58%↑AUC 80%
      Erlotinib↓ AUC 57.6%–80%↑AUC 66%
      AfatinibUnlikely or negligibleUnlikely or negligible
      Osimertinib↓ AUC 78%↑ AUC 24%, ↓ Cmax 20%
      AumolertinibUnknownUnknown
      Furmonertinib↓ AUC 86%, ↓ Cmax 60%↑ AUC 1.4× (41%), ↑ Cmax 23%
      IcotinibUnknown↑ AUC 67%–84%
      DacomitinibUnknownUnknown
      LazertinibUnknownUnknown
      EGFR exon 20 insertion
      Sunvozertinib (DZD9008)Strong CYP3A4 inhibitors and inducers were stopped before administration of sunvozertinib per protocol
      Mobocertinib↓ AUC 92%↑ AUC 374%–419%
      ALK inhibitors
      AlectinibNo effects observed
      Brigatinib↓ AUC 80%, ↓ Cmax 60%↑ AUC 101%, ↑ Cmax 21%
      Lorlatinib↓ AUC 85%, ↓ Cmax 76%↑ AUC 42%, ↑ Cmax 24%
      ROS1 inhibitors
      Crizotinib↓ AUC 84%, ↓ Cmax 79%↑ AUC 216%, ↑ Cmax 44%
      Entrectinib↓ AUC 77%, ↓ Cmax 56%↑ AUC 6×, ↑ Cmax 1.7×
      RepotrectinibExcluded from studyExcluded from study
      TaletrectinibExcluded from studyExcluded from study
      MET inhibitors
      Capmatinib↓ AUC 67%, ↓ Cmax 56%↑ AUC 421%, ↑ Cmax 0%
      TepotinibUnknownUnknown
      RET inhibitors
      Selpercatinib↓ AUC 87%, ↓ Cmax 70%↑ AUC 133%, ↑ Cmax 30%
      Pralsetinib↓ AUC 68%, ↓ Cmax 30%↑ AUC 251%, ↑ Cmax 84%
      KRAS p.G12C mutations
      Sotorasib↓ AUC 51%, ↓ Cmax 25%
      Adagrasib↓ AUC 95%, ↓ Cmax 88%↑ AUC 400%, ↑ Cmax 200%
      HER2 ± HER4 inhibitors
      Tucatinib↓ AUC 0.6×, ↓ Cmax 0.5×↑ AUC 1.3×, ↑ Cmax 1.3×
      Neratinib↓ AUC 87%, ↓ Cmax 76%↑ AUC 481%, ↑ Cmax 321%
      NTRK inhibitor
      Larotrectinib↓ AUC 81%, ↓ Cmax 71%↑ AUC 4.3×, ↑ Cmax 2.8×
      MEK/BRAF inhibitors
      Dabrafenib↓ AUC 34%↑ AUC 71%
      TrametinibUnknownUnknown
      Cobimetinib↓ AUC 83%↑ AUC 90%
      Vemurafenib↓ AUC 40%NA
      EncorafenibUnknown↑ AUC 200%, ↑ Cmax 68%,
      BinimetinibUnknownUnknown
      Multiple-target TKIs
      Cabozantinib↓ AUC 77%↑ AUC 38%
      AnlotinibUnknownUnknown
      AUC, area under the curve; NA, not applicable; TKI, tyrosine kinase inhibitor.
      Table 3Dose-Attenuation Recommendations Related to CYP3A4 on the basis of Package Inserts
      TKIsDose-Attenuation Recommendations
      EGFR inhibitors
      Gefitinib
      • •
        Strong CYP3A4 inducers: ↑ dose to 500 mg daily
      • •
        Strong CYP3A4 inhibitors: use with caution
      Erlotinib
      • •
        Strong CYP3A4 inducers: consider an alternative agent, increase dose to a maximum of 450 mg daily
      • •
        Strong CYP3A4 inhibitors: use with caution
      AfatinibNot applicable
      Osimertinib
      • •
        Strong CYP3A4 inducers: avoid use if possible, increase to max 160 mg daily and then resume 80 mg daily 3 wk after discontinuing inducer
      • •
        Strong CYP3A4 inhibitors: no clinically relevant effect observed, use with caution
      Aumolertinib
      • •
        Not available
      Furmonertinib
      • •
        Strong CYP3A4 inducers: caution
      • •
        Strong CYP3A4 inhibitors: generally safe and well tolerated; no strong data to suggest dose adjustment yet.
      Icotinib
      • •
        Not available
      Dacomitinib
      • •
        Not available
      Lazertinib
      • •
        Strong CYP3A4 inducers: not well studied, avoid use if possible
      • •
        Strong CYP3A4 inhibitors: not well studied. in the absence of an alternative drug, monitor closely for signs of changes in the tolerability of lazertinib (e.g., QTc prolongation, cardiotoxicity, keratitis, LFTs)
      EGFR exon 20 insertion
      Mobocertinib
      • •
        Strong CYP3A inducers: avoid use
      • •
        Strong CYP3A inhibitors: avoid use; if unavoidable, reduce the dose by approximately 50%.
      Sunvozertinib (DZD9008)
      • •
        On the basis of in vitro data and clinical exposure, DZD9008 DDI risk is considered unlikely to cause clinically relevant hepatic drug interactions at clinically relevant concentrations through inhibition or induction of cytochrome P450 enzyme activity
      ALK inhibitors
      AlectinibNot applicable
      Brigatinib
      • •
        Strong CYP3A4 inducers: avoid use; if unavoidable, increase dose by 30 mg increments once daily up to maximum of twice the original dose
      • •
        Strong CYP3A4 inhibitors: avoid use; if unavoidable, decrease dose by 50%
      Lorlatinib
      • •
        Strong CYP3A inducers: Contraindicated (potential risk of hepatotoxicity); discontinue strong CYP3A inducers for 3 plasma half-lives before initiating.
      • •
        Strong CYP3A inhibitors: avoid use; if unavoidable, reduce starting dose from 100 mg once daily to 75 mg once daily. If starting dose is reduced to 75 mg owing to adverse reactions, then reduce further to 50 mg before starting strong CYP3A inhibitor.
      ROS1 inhibitors
      Crizotinib
      • •
        Strong CYP3A4 inducers: avoid use
      • •
        Strong CYP3A4 inhibitors: avoid use; if unavoidable, reduce dose to 250 mg once daily
      Entrectinib
      • •
        Strong CYP3A4 inducers: avoid use
      • •
        Strong CYP3A4 inhibitors: > 12 yo + BSA > 1.5 m2, reduce dose to 100 mg once daily if cannot be avoided; if BSA ≤ 1.5 m2 avoid use
      RepotrectinibStrong CYP3A4 inducers and inhibitors were excluded from the protocol
      TaletrectinibStrong CYP3A4 inducers and inhibitors were excluded from the protocol
      MET inhibitors
      Capmatinib
      • •
        Strong CYP3A4 inducers: avoid use
      • •
        Strong CYP3A4 inhibitors: closely monitor for adverse reactions
      Tepotinib
      • •
        Strong CYP3A4 inducers: avoid use
      • •
        Strong CYP3A4 inhibitors: avoid use
      RET inhibitors
      Selpercatinib
      • •
        Strong CYP3A4 inducers: avoid use
      • •
        Strong CYP3A4 inhibitors: avoid use; if unavoidable, then reduce 160 mg twice daily dose to 80 mg twice daily and 120 mg twice daily dose to 40 mg twice daily
      Pralsetinib
      • •
        Strong CYP3A4 inducers: double the dose on day 7 of the inducer until 14 d after discontinuation of inducer
      • •
        Strong CYP3A4 inhibitors: avoid use; if unavoidable, then reduce 400 mg once daily to 200 mg, 300 mg once daily to 200 mg, 200 mg once daily to 100 mg
      KRAS p.G12C mutations
      Sotorasib
      • •
        Strong CYP3A4 inducers: avoid use
      Adagrasib
      • •
        Strong CYP3A4 inhibitors and inducers: early in study, use an alternative concomitant medication
      HER2 ± HER4 inhibitors
      Tucatinib
      • •
        Strong CYP3A4 inducers: avoid use
      • •
        Strong CYP2C8 inhibitors: avoid use; if unavoidable, then reduce 100 mg twice daily
      Neratinib
      • •
        Strong CYP3A4 inducers: avoid use
      • •
        Strong CYP3A4 inhibitors: avoid use
      NTRK inhibitor
      Larotrectinib
      • •
        Strong CYP3A4 inducer: avoid use; if unavoidable, then double the dose
      • •
        Strong CYP3A4 inhibitor: avoid use; if unavoidable, then reduce the dose by 50%
      MEK/BRAF inhibitors
      Dabrafenib
      • •
        Strong CYP3A4 inhibitors: avoid use; if unavoidable, then monitor closely for adverse reactions
      Trametinib
      • •
        n combination with dabrafenib, refer to dabrafenib labeling for dose adjustments
      Cobimetinib
      • •
        Strong CYP3A4 inducers: avoid use, may decrease systemic exposure by more than 80%
      • •
        Strong CYP3A4 inhibitors: avoid use, especially in patients already taking reduced doses (e.g., 40 or 20 mg daily)
      Vemurafenib
      • •
        Strong CYP3A4 inducers: avoid use; if unavoidable, increase dose by 240 mg (one tablet)
      • •
        Strong CYP3A4 inhibitors: avoid use, in vitro reveals as a CYP3A4 substrate but no data in vivo
      Encorafenib
      • •
        Strong CYP3A4 inducers: avoid coadministration. Current data suggest autoinduction owing to reduced steady-state concentrations compared with initiation concentrations after the first dose.
      • •
        Strong CYP3A4 inhibitors: reduce dose by one-third. After inhibitor has been discontinued for three to five half-lives, resume normal dose.
      Binimetinib
      • •
        No clinically important drug interactions have been observed and are not a substrate of CYP3A4
      Multiple-target TKIs
      Cabozantinib
      • •
        Strong CYP3A4 inducers: increase the daily dose by 20 mg
      • •
        Strong CYP3A4 inhibitors: reduce the daily dose by 20 mg
      Anlotinib
      • •
        Not available
      BSA, body surface area; DDI, drug-drug interaction; LFT, liver function test; TKI, tyrosine kinase inhibitor.

      EGFR Inhibitors (Gefitinib, Erlotinib, Afatinib, Osimertinib, Aumolertinib, Furmonertinib, Dacomitinib, Sunvozertinib, Lazertinib)

      Most EGFR inhibitors are major substrates of CYP3A4 with the exception of afatinib, dacomitinib, and lazertinib. Coadministration of ritonavir-boosted nirmatrelvir with EGFR inhibitors is expected to moderately increase the AUCs of these TKIs. In trials, coadministration of itraconazole and ketoconazole, strong CYP 3A4 inhibitors, increased the AUC of these TKIs between 66% and 84%.
      Food and Drug Administration
      GILOTRIF® (afatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf
      Date accessed: September 2, 2022
      , 
      Food and Drug Administration
      IRESSA (gefitinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206995s003lbl.pdf
      Date accessed: September 2, 2022
      , 
      Food and Drug Administration
      TAGRISSO™ (osimertinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf
      Date accessed: September 2, 2022
      , 
      Food and Drug Administration
      TARCEVA® (erlotinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf
      Date accessed: September 2, 2022
      , 

      Food and Drug Administration. VIZIMPRO® (dacomitinib) FDA package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf. Accessed

      Because the therapy duration for ritonavir-boosted nirmatrelvir is relatively short, the moderate increases in AUCs may put patients at risk for common side effects, including cutaneous adverse drug reactions, and gastrointestinal side effects, which may require monitoring.

      EGFR Exon 20 Insertion (Mobocertinib, Sunvozertinib)

      Mobocertinib is a major substrate of CYP 3A, and coadministration with itraconazole and ketoconazole increased the AUC by 374% to 419%.
      Food and Drug Administration
      EXKIVITY™ (mobocertinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215310s000lbl.pdf
      Date accessed: September 2, 2022
      Strong CYP 3A4 inhibitors such as ritonavir-boosted nirmatrelvir will likely produce similar effects in the AUC and predispose patients to increased risk of adverse events (e.g., interstitial lung disease [ILD], pneumonitis, cardiac toxicity, and diarrhea). Sunvozertinib is also a major substrate of CYP 3A4; however, DDI data are limited because strong 3A4 inhibitors and inducers were excluded in trials.

      HER2 ± HER4 Inhibitors (Tucatinib, Neratinib)

      Neratinib is a major substrate of CYP 3A4 in contrast to tucatinib, which is a minor substrate. Despite tucatinib being a minor CYP 3A4 substrate, 200 mg twice-daily administration of itraconazole increased tucatinib’s AUC and Cmax by 30%.
      Food and Drug Administration
      TUKYSATM (tucatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213411s000lbl.pdf
      Date accessed: September 2, 2022
      Coadministration of neratinib with ketoconazole increased the AUC by 481% and Cmax by 321%. These increases in drug exposure can increase risk for key adverse class effects (e.g., severe diarrhea and hepatotoxicity).

      ALK Inhibitors (Alectinib, Brigatinib, Lorlatinib)

      All ALK inhibitors are major substrates of CYP 3A4. Of note, there was no major change with alectinib in the presence of strong CYP 3A4 inhibitors and inducers. Coadministration with itraconazole increased the AUC of brigatinib and lorlatinib by 101% and 42%, respectively.
      Food and Drug Administration
      ALUNBRIG® (brigatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208772s008lbl.pdf
      Date accessed: September 2, 2022
      ,

      Food and Drug Administration. LORBRENA® (lorlatinib) FDA package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210868s004lbl.pdf. Accessed 02 September 2, 2022.

      Given that ritonavir-boosted nirmatrelvir has similar or possibly higher CYP 3A4 inhibiting potential as itraconazole and posaconazole, the concomitant use of ALK inhibitors and ritonavir-boosted nirmatrelvir will result in similar supratherapeutic concentrations of ALK inhibitors and associated adverse effects (e.g., hepatotoxicity, pneumonitis, ILD, visual disturbances).

      ROS1 Inhibitors (Crizotinib, Entrectinib, Repotrectinib, Taletrectinib)

      Both crizotinib and entrectinib are major substrates of CYP 3A4. Coadministration with ketoconazole and itraconazole has led to increased AUCs in crizotinib and entrectinib by 216% and 500%, respectively.
      Food and Drug Administration
      ROZLYTREK (entrectinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf
      Date accessed: September 2, 2022
      ,
      Food and Drug Administration
      XALKORI® (crizotinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202570s030lbl.pdf
      Date accessed: September 2, 2022
      This makes entrectinib the most vulnerable to strong CYP 3A4 inhibition by ritonavir-boosted nirmatrelvir with the highest risk for causing adverse effects such as hepatotoxicity, QTc prolongation, ILD, and visual loss. DDI data are limited for repotrectinib and taletrectinib because strong CYP 3A4 inducers and inhibitors were excluded from trials.

      MET Inhibitors (Capmatinib, Tepotinib)

      Capmatinib and tepotinib are both major substrates of CYP 3A4. Coadministration of itraconazole increased the AUC of capmatinib by 421%.
      Food and Drug Administration
      TABRECTATM (capmatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213591s000lbl.pdf
      Date accessed: September 2, 2022
      This increased drug exposure can lead to a considerable risk of adverse events (e.g., ILD, hepatotoxicity, photosensitivity). The effect of strong CYP 3A4 inhibitors on tepotinib has not been studied, but on the basis of the manufacturer’s package insert, concomitant use with dual strong CYP 3A4 inhibitors and P-gp inhibitors should be avoided.

      RET Inhibitors (Selpercatinib, Pralsetinib)

      Both selpercatinib and pralsetinib are major substrates of CYP 3A4. In clinical trials, the coadministration of itraconazole with selpercatinib and pralsetinib increased the AUCs of these agents by 133% and 251%, respectively.
      Food and Drug Administration
      GAVRETO™ (pralsetinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214701s000lbl.pdf
      Date accessed: September 2, 2022
      ,
      Food and Drug Administration
      RETEVMOTM (selpercatinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf
      Date accessed: September 2, 2022
      Increased drug exposure can potentially lead to an increased risk of adverse effects (e.g., hepatotoxicity, QTc prolongation, hemorrhagic events, impaired wound healing).

      MEK/BRAF Inhibitors (Dabrafenib, Trametinib, Cobimetinib/Vemurafenib, Encorafenib/Binimetinib)

      Trametinib, vemurafenib, and binimetinib are not substrates of CYP 3A4 and unlikely to be affected by strong CYP 3A4 inhibition by ritonavir-boosted nirmatrelvir. Dabrafenib is a major substrate of CYP 3A4 and coadministration with ketoconazole increased the AUC of dabrafenib by 71%.
      Food and Drug Administration
      TAFINLAR® (dabrafenib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s010lbl.pdf
      Date accessed: September 2, 2022
      Cobimetinib coadministration with itraconazole increased AUC by 90%. Encorafenib coadministration with posaconazole increased AUC by 200% and Cmax by 68%. Increases in concentrations of these agents may pose a higher risk of adverse effects (e.g., diarrhea, nausea, fatigue, and electrolyte abnormalities).

      NTRK Inhibitor (Larotrectinib)

      Larotrectinib is a major substrate of CYP 3A4, and coadministration with itraconazole increased the AUC of larotrectinib by 4.3 times.
      Food and Drug Administration
      VITRAKVI® (larotrectinib) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/211710s004lbl.pdf
      Date accessed: September 2, 2022
      This increase in drug exposure may magnify the risk for central nervous system adverse events (dizziness, cognitive impairment, mood disorders, sleep disturbances), fractures, and hepatotoxicity.

      KRAS p.G12C Mutations (Sotorasib, Adagrasib)

      Sotorasib is a major substrate of CYP 3A4; however, no clinically meaningful effect on the exposure of sotorasib was observed after coadministration with itraconazole. Adagrasib is also a major substrate for CYP 3A4, and the presence of strong CYP 3A4 inhibition by itraconazole can lead to an AUC increase of 400%. There is an expected corresponding increase, but different magnitude of impact on AUC with ritonavir-boosted nirmatrelvir co-administration.

      Multiple-Target TKIs (Cabozantinib, Anlotinib)

      Cabozantinib and anlotinib are both major substrates of CYP 3A4. Co-administration with ketoconazole for 27 days increased AUC of cabozantinib by 38%. Data are limited on the effect of co-administration of strong CYP 3A4 inhibitors on anlotinib.

      Impact of Ritonavir-Boosted Nirmatrelvir on Supportive Care Medications

      Most often, patients diagnosed with having lung cancer receive supportive care medications for managing associated cancer- and treatment-induced toxicities. Patients receiving lung cancer TKI often experience nausea/vomiting, gastrointestinal toxicities (e.g., diarrhea), and dermatologic toxicities that can affect their quality of life. In this section, we will focus on the potential DDI of ritonavir-boosted nirmatrelvir on various supportive care medications.

      Nausea and Vomiting

      Aprepitant, prednisone, and dexamethasone are all major substrates of CYP 3A4, whereas granisetron and ondansetron are minor substrates. Co-administration of strong CYP 3A4 inhibitors with aprepitant is not recommended because it can cause an increase in serious adverse events (e.g., hypotension and bradycardia). Concomitant use of strong CYP 3A4 inhibitors with corticosteroids (e.g., dexamethasone, prednisone) should be used with caution, for a limited amount of time, and patient monitoring for side effects is recommended. The 5-HT3 inhibitors (e.g., granisetron, ondansetron) are the least affected by strong CYP 3A4 inhibitors and should be used first line before other antiemetics are considered. Adverse effects associated with 5-HT3 inhibitors include constipation, headaches, and QTc prolongation, and they may be exacerbated with concomitant ritonavir-boosted nirmatrelvir.

      Gastrointestinal Toxicities

      Loperamide is a minor substrate of CYP 3A4, whereas diphenoxylate/atropine is not a substrate of CYP 3A4. Co-administration of loperamide with strong CYP 3A4 inhibitors such as ritonavir has resulted in an increase of AUC from 104 ± 60 h × pmol/mL after placebo to 276 ± 68 h.
      • Tayrouz Y.
      • Ganssmann B.
      • Ding R.
      • et al.
      Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement.
      Clin Pharmacol Ther. 2001; 70: 405-414
      Patients receiving loperamide and ritonavir-boosted nirmatrelvir should be monitored for nausea and constipation. Diphenoxylate/atropine is not expected to have clinically relevant changes in AUC during co-administration with strong CYP 3A4 inhibitors.

      Dermatologic Toxicities

      Patients receiving TKI most often receive antibiotics, antipyretics, antihistamines, and topical agents for managing dermatologic toxicities. Within the tetracycline family, only tetracycline is expected to interact with ritonavir-boosted nirmatrelvir, as it is a minor substrate of CYP 3A4.
      Food and Drug Administration
      Tetracycline FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/060704s035lbl.pdf
      Date accessed: September 2, 2022
      Drug exposure is not expected to change substantially with doxycycline and tetracycline during the co-administration of strong CYP 3A4 inhibitors.
      Food and Drug Administration
      Tetracycline FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/060704s035lbl.pdf
      Date accessed: September 2, 2022
      ,
      Food and Drug Administration
      DORYX® (doxycycline hyclate) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050795s005lbl.pdf
      Date accessed: September 2, 2022
      Erythromycin is a major substrate of CYP 3A4, and co-administration of strong CYP 3A4 inhibitors should be avoided in patients at increased risk of adverse effects (e.g., QTc prolongation).
      Food and Drug Administration
      Erythromycin ethylsuccinate FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050207s071lbl.pdf
      Date accessed: September 2, 2022
      Clindamycin is a substrate of CYP 3A4 and co-administration of strong CYP 3A4 inhibitor may also increase the concentration of clindamycin.
      Food and Drug Administration
      Cleocin HCl® (clindamycin hydrochloride) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/050162s092s093lbl.pdf
      Date accessed: September 2, 2022
      Monitoring for adverse effects associated with clindamycin is recommended. Triamcinolone is a substrate of CYP 3A4, and coadministration of strong CYP 3A4 inhibitors may lead to serious glucocorticoid toxicities (e.g., iatrogenic Cushing’s syndrome), even with topical administration.
      Food and Drug Administration
      Kenalog CREAM (triamcinolone acetonide) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/pre96/011601s036lbl.pdf
      Date accessed: September 2, 2022
      Loratadine is most often used for managing pruritus related to oral TKIs. CYP 3A4 is not a major part of loratadine metabolism, suggesting it is safe to use in conjunction with ritonavir-boosted nirmatrelvir.
      Food and Drug Administration
      CLARITIN® (loratadine) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20641s7lbl.pdf
      Date accessed: September 2, 2022
      Last, antipyretics such as ibuprofen and acetaminophen are not metabolized by the CYP 3A4 system and thus are unaffected by concomitant ritonavir-boosted nirmatrelvir.
      Food and Drug Administration
      Acetaminophen FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204767s000lbl.pdf
      Date accessed: September 2, 2022
      ,
      Food and Drug Administration
      Motrin® (ibuprofen) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017463s105lbl.pdf
      Date accessed: September 2, 2022

      Cancer-Associated Pain

      Patients with lung cancer most often require analgesics to relieve their cancer-associated pain. Among opioids, tramadol, methadone, hydrocodone, oxycodone, fentanyl, and buprenorphine are major substrates of CYP3A4, and coadministration of strong CYP 3A4 inhibitors should be carefully monitored for potential adverse effects (e.g., life-threatening respiratory depression, sedation, hypotension), and a dose reduction should be considered.
      Food and Drug Administration
      Ultram ER (tramadol hydrochloride) FDA Package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021692s015lbl.pdf
      Date accessed: December 2, 2022
      , 

      Food and Drug Administration. DOLOPHINE® (methadone hydrochloride) FDA package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/006134s045lbl.pdf. Accessed September 2, 2022.

      , 
      Food and Drug Administration
      ZOHYDRO® ER (hydrocodone bitartrate) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202880s020lbl.pdf
      Date accessed: December 2, 2022
      , 
      Food and Drug Administration
      OXYCONTIN® (oxycodone hydrochloride) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022272s046lbl.pdf
      Date accessed: December 2, 2022
      , 
      Food and Drug Administration
      Duragesic (fentanyl transdermal system) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/019813s081lbl.pdf
      Date accessed: December 2, 2022
      , 
      Food and Drug Administration
      BUTRANS (buprenorphine) Transdermal Patch FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021306s015s019lbl.pdf
      Date accessed: December 2, 2022
      Codeine is primarily metabolized to morphine by CYP 2D6 and norcodeine by CYP 3A4, and coadministration with strong CYP3A4 inhibitors may result in an increase in codeine plasma concentrations with subsequently greater metabolism by CYP 2D6 resulting in greater morphine levels; thus, a dose reduction should be considered.
      Food and Drug Administration
      Codeine sulfate FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022402s014lbl.pdf
      Date accessed: December 2, 2022
      In contrast, oxymorphone, tapentadol, morphine, and hydromorphone are not metabolized by CYP 3A4 and therefore are not expected to considerably increase plasma concentrations, suggesting they are safe to use in conjunction with ritonavir-boosted nirmatrelvir.
      Food and Drug Administration
      OPANA® ER (oxymorphone hydrochloride) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021610s028lbl.pdf
      Date accessed: December 2, 2022
      , 
      Food and Drug Administration
      NUCYNTA® (tapentadol) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022304s023lbl.pdf
      Date accessed: December 2, 2022
      , 
      Food and Drug Administration
      Morphine sulfate FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022207s004lbl.pdf
      Date accessed: December 2, 2022
      , 
      Food and Drug Administration
      DILAUDID® INJECTION (hydromorphone hydrochloride) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019034s035lbl.pdf
      Date accessed: December 2, 2022
      As mentioned previously, ibuprofen and acetaminophen, used as both antipyretics and nonopioid analgesics, are not metabolized by the CYP 3A4 system and thus are unaffected by concomitant use of ritonavir-boosted nirmatrelvir.
      Food and Drug Administration
      Acetaminophen FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204767s000lbl.pdf
      Date accessed: September 2, 2022
      ,
      Food and Drug Administration
      Motrin® (ibuprofen) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017463s105lbl.pdf
      Date accessed: September 2, 2022

      Cancer-Associated Venous Thromboembolism

      Direct oral anticoagulants and low molecular weight heparin are widely used and preferred to treat cancer-associated venous thromboembolisms in patients with lung cancer. Among preferred direct oral anticoagulants, apixaban and rivaroxaban are major substrates of CYP 3A4, whereas edoxaban is not a substrate of CYP 3A4 and thus unlikely unaffected by CYP 3A4 inhibition.
      Food and Drug Administration
      ELIQUIS (apixaban) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf
      Date accessed: December 2, 2022
      , 
      Food and Drug Administration
      XARELTO® (rivaroxaban) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202439s017lbl.pdf
      Date accessed: December 2, 2022
      , 
      Food and Drug Administration
      SAVAYSA (edoxaban) FDA package insert.
      https://www.accessdata.fda.gov/spl/data/ddafd408-bb00-4aac-b7fb-aa2c8bb8de88/ddafd408-bb00-4aac-b7fb-aa2c8bb8de88.xml#S7.1
      Date accessed: December 2, 2022
      If apixaban is co-administered with ritonavir-boosted nirmatrelvir, a dose reduction to 2.5 mg twice daily should be made, along with close monitoring of signs and symptoms of bleeding. There is no current dose-reduction recommendation for rivaroxaban coadministration with CYP 3A4 inhibitors; however, use should be avoided if possible, and if it is unavoidable, signs and symptoms of bleeding should be closely monitored. Enoxaparin and dalteparin are not substrates of CYP 3A4 and thus are not affected by coadministration of ritonavir-boosted nirmatelvir.
      Food and Drug Administration
      Lovenox (enoxaparin sodium injection) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020164s083lbl.pdf
      Date accessed: December 2, 2022
      ,
      Food and Drug Administration
      FRAGMIN® (dalteparin sodium) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020287s072lbl.pdf
      Date accessed: December 2, 2022
      In some cases, clinicians may use dabigatran, fondaparinux, and warfarin. The R-enantiomer of warfarin is metabolized by CYP 3A4; thus, coadministration of warfarin with ritonavir-boosted nirmatrelvir is discouraged.
      Food and Drug Administration
      COUMADIN (warfarin sodium) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf
      Date accessed: December 2, 2022
      Dabigatran and fondaparinux are not metabolized by CYP 3A4 and therefore are unaffected by concomitant use of ritonavir-boosted nirmatrelvir.
      Food and Drug Administration
      FRAGMIN® (dalteparin sodium) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020287s072lbl.pdf
      Date accessed: December 2, 2022
      ,
      Food and Drug Administration
      ARIXTRA (fondaparinux sodium) FDA package insert.
      https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021345s019lbl.pdf
      Date accessed: December 2, 2022

      Discussion

      In this review, we have identified a number of potential DDIs between lung cancer TKIs and ritonavir-boosted nirmatrelvir. Lung cancer TKIs are most often substrates of CYP 3A4, and knowing that ritonavir-boosted nirmatrelvir is a strong inhibitor of CYP 3A4, potential DDIs can occur when co-administered. Although ritonavir is a strong inhibitor of CYP 3A4, the degree of CYP 3A4 inhibition varies depending on the TKI and the dose and duration of the inhibitor. Clinical pharmacologic studies have summarized the degree of drug concentration increase. For instance, coadministration of capmatinib and itraconazole (a strong CYP 3A4 inhibitor) can result in a 421% increase in AUC, whereas coadministration of osimertinib and itraconazole only resulted in a 24% increase in AUC. Because strong CYP 3A4 inhibitors can cause changes to exposure of TKI and potentiate adverse effects, the concomitant use of such agents with TKI is not recommended and should be identified and avoided if possible. Of note, a few of the TKI are known substrates of CYP 3A4 and may potentially have increased exposure when co-administered with ritonavir-boosted nirmatrelvir; however, there is a lack of published pharmacologic studies that would allow a thorough evaluation of the impact of drug exposure owing to strong CYP 3A4 inducers or inhibitors. The current manufacturer’s prescribing information does not contraindicate the concurrent use of ritonavir-boosted nirmatrelvir with CYP 3A4 inhibitors, such as in other ritonavir-based therapies, but it recommends monitoring. Nevertheless, if ritonavir-boosted nirmatrelvir must be used with potentially interacting TKI, careful monitoring for toxicities is advised.
      DDIs are most often observed within oncology practice, especially with the wider use of oral TKI to treat various malignancies, such as lung cancers. Nevertheless, such interactions may also affect efficacy and safety of the various TKIs. For example, coadministration of imatinib (a drug to treat chronic myelogenous leukemia) and voriconazole (a strong CYP 3A4 inhibitor) is known to cause severe pustular eruption.
      • Gambillara E.
      • Laffitte E.
      • Widmer N.
      • et al.
      Severe pustular eruption associated with imatinib and voriconazole in a patient with chronic myeloid leukemia.
      Dermatology. 2005; 211: 363-365
      On the basis of the recommendation of the FDA, drugs that increase the AUC of sensitive index substrates of CYP 3A by five or more folds are considered as strong inhibitors of CYP 3A4.
      Food and Drug Administration
      Drug development and drug interactions | Table of substrates, inhibitors and inducers.
      https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
      Date accessed: September 2, 2022
      These drugs include the various antifungals (itraconazole, ketoconazole, posaconazole, voriconazole), antibiotics (clarithromycin), diltiazem, several antivirals (ritonavir, nelfinavir, boceprevir, telaprevir), and neurologic agents, such as nefazodone. Grapefruit juice, grapefruit, and Seville oranges are also known to strongly inhibit CYP 3A4. Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index substrates by greater than or equal to fivefold, greater than or equal to twofold to less than fivefold, and greater than or equal to 1.25-fold to less than twofold, respectively.
      Food and Drug Administration
      Drug development and drug interactions | Table of substrates, inhibitors and inducers.
      https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
      Date accessed: September 2, 2022
      Nevertheless, the extent to which strong CYP 3A4 inhibitors affects the exposure of each TKI may vary between each drug. This article has provided an extensive review of the impact of strong CYP3A4 inhibitors that can be extrapolated to ritonavir-boosted nirmatrelvir.
      Current guidelines of the National Institutes of Health stated that because ritonavir-boosted nirmatrelvir is the only highly effective oral antiviral for COVID-19, DDIs resulting in increased drug exposure should not preclude the use of this medication if they can be safely managed.

      National Institutes of Health. COVID-19 treatment guidelines: ritonavir-boosted nirmatrelvir (paxlovid), https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir%5fpaxlovid-/. Accessed September 2, 2022.

      In view of the need to initiate ritonavir-boosted nirmatrelvir for treatment of COVID-19, clinicians may choose to temporarily interrupt TKI therapies in view of the interaction. Furthermore, in view that there is an increased use of off-label prolonged therapy (as long as 10 d total) of ritonavir-boosted nirmatrelvir in clinical practice owing to COVID-19 rebound that may happen as early as day 7 (3.53%) after initiation of ritonavir-boosted nirmatrelvir,
      • Wang L.
      • Berger N.A.
      • Davis P.B.
      • Kaelber D.C.
      • Volkow N.D.
      • Xu R.
      COVID-19 rebound after paxlovid and molnupiravir during January–June 2022. medRxiv.
      https://www.medrxiv.org/content/10.1101/2022.06.21.22276724v1
      Date accessed: September 2, 2022
      prolonged treatment should be evaluated on a case-by-case scenario on the basis of risk factors and patient-specific factors to determine whether a prolonged or second 5-day course is necessary. With prolonged use of ritonavir-boosted nirmatrelvir, it is important to ensure that any modification with TKI should be continued for 3 additional days after the end of ritonavir-boosted nirmatrelvir.
      Temporary reduction of TKI doses is a potential strategy for managing the drug interaction between strong CYP 3A4 inhibition. Inhibition of this enzyme system can result in higher exposure of TKI and might allow for lower dosages to minimize adverse effects and reduce health care costs. In an open-label, crossover study, investigators compared the pharmacokinetics of monotherapy erlotinib 150 mg once daily (control arm) with erlotinib 75 mg daily plus ritonavir 200 mg daily (intervention arm).
      • Boosman R.J.
      • de Gooijer C.J.
      • Groenland S.L.
      • et al.
      Ritonavir-boosted exposure of kinase inhibitors: an open label, cross-over pharmacokinetic proof-of-concept trial with erlotinib.
      Pharm Res. 2022; 39: 669-676
      The authors concluded that the pharmacokinetic exposure at a dose of 75 mg erlotinib when combined with ritonavir was similar to 150 mg erlotinib. In fact, the authors concluded that ritonavir boosting is a promising strategy to reduce erlotinib treatment costs and provides a rationale for other expensive therapies metabolized by CYP 3A4. In contrast, if the decision is to temporary hold oral TKI while patient is receiving ritonavir-boosted nirmatrelvir, it is recommended that the oral TKI should be held for 3 additional days, in view of the inhibitor effect that can last 3 additional days post-drug administration.
      An alternative strategy to holding TKI or making TKI dose adjustments would be to use the other oral antiviral with emergency use authorization to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), molnupiravir. In contrast to ritonavir-boosted nirmatrelvir, molnupiravir is a nucleoside analogue that inhibits SARS-CoV-2 replication by inducing RNA mutagenesis.

      Kabinger F, Stiller C, Schmitzová J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol 09. 2021;28:740–746.

      Molnupiravir does not require a pharmacokinetic booster (i.e., ritonavir) and is not an inhibitor or an inducer of any major human CYP enzymes; therefore, it will likely not interact with TKI by CYP enzymes.

      Atmar RL, Finch N. New perspectives on antimicrobial agents: molnupiravir and Nirmatrelvir/Ritonavir for treatment of COVID-19. Antimicrob Agents Chemother. 08 16 2022;66:e0240421.

      With respect to efficacy, the phase 3 portion of the clinical trial (MOVe-OUT) revealed that molnupiravir had an absolute reduction of hospitalization or death by 3% and adjusted relative risk reduction of 30% compared with placebo.

      Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 02 10 2022;386:509–520.

      In comparison, the phases 2 to 3 randomized clinical trial that evaluated ritonavir-boosted nirmatrelvir revealed a 5.8% absolute reduction and 89% relative risk reduction in hospitalization or death owing to SARS-CoV-2.

      Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 02 10 2022;386:509–520.

      Last, we have also observed that TKI within the same class may have different DDI potential. Providers who are newly initiating oral TKI must consider the potential risks of DDI with other medications for treatment of comorbid conditions. Nevertheless, for patients who have already been stabilized with a specific TKI, it may be challenging to switch from one TKI to another in view of the temporary DDI with ritonavir-boosted nirmatrelvir. Providers must exercise their professional judgment to decide on how best to concurrently administer ritonavir-boosted nirmatrelvir and TKI to prevent any adverse drug events. Providers should also consider consulting an oncology pharmacist to optimize the dosing strategies of the TKI.
      In conclusions, with the recent advancements in COVID-19 treatments, the wide use of ritonavir-boosted nirmatrelvir may increase the risk of patients with lung cancer for unwanted morbidities owing to DDIs. In this review, we have identified a number of potential DDIs between lung cancer TKIs and ritonavir-boosted nirmatrelvir. Nevertheless, the impact of the interaction between these TKIs and ritonavir-boosted nirmatrelvir varies largely on the basis of the susceptibility of CYP 3A4 inhibition of the TKI. Clinicians must be diligent in assessing the risk of interactions before the prescribing of ritonavir-boosted nirmatrelvir in patients with lung cancer and should consider strategies to overcome DDIs and consulting an oncology pharmacist to optimize the dosing of the TKI.

      CRediT Authorship Contribution Statement

      Kaleem Anwar: Data curation, Methodology, Writing of original draft.
      Lee Nguyen: Review and editing.
      Misako Nagasaka: Review and editing.
      Sai-Hong Ignatius Ou: Conceptualization, Review and editing.
      Alexandre Chan: Conceptualization, Methodology, Supervision, Review and editing.

      Supplementary Data

      References

      1. National Institutes of Health. COVID-19 treatment guidelines: ritonavir-boosted nirmatrelvir (paxlovid), https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir%5fpaxlovid-/. Accessed September 2, 2022.

        View in Article
        • Food and Drug Administration
        Fact sheet for healthcare providers. Emergency use authorization for paxlovid.
        https://www.fda.gov/media/155050/download
        Date accessed: September 2, 2022
        View in Article

      3. Thomson RJ, Moshirfar M, Ronquillo Y. Tyrosine kinase inhibitors. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. https://www.ncbi.nlm.nih.gov/books/NBK563322/?report=classic. Accessed September 2, 2022.

        View in Article

      4. NCCN. Non-small cell lung cancer, Version 4. 2022. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed September 3, 2022.

        View in Article
        • Food and Drug Administration
        GILOTRIF® (afatinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        IRESSA (gefitinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206995s003lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        TAGRISSO™ (osimertinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        TARCEVA® (erlotinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf
        Date accessed: September 2, 2022
        View in Article

      9. Food and Drug Administration. VIZIMPRO® (dacomitinib) FDA package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf. Accessed

        View in Article
        • Food and Drug Administration
        EXKIVITY™ (mobocertinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215310s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        TUKYSATM (tucatinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213411s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        ALUNBRIG® (brigatinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208772s008lbl.pdf
        Date accessed: September 2, 2022
        View in Article

      13. Food and Drug Administration. LORBRENA® (lorlatinib) FDA package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210868s004lbl.pdf. Accessed 02 September 2, 2022.

        View in Article
        • Food and Drug Administration
        ROZLYTREK (entrectinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        XALKORI® (crizotinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202570s030lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        TABRECTATM (capmatinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213591s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        GAVRETO™ (pralsetinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214701s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        RETEVMOTM (selpercatinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        TAFINLAR® (dabrafenib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s010lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        VITRAKVI® (larotrectinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/211710s004lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Tayrouz Y.
        • Ganssmann B.
        • Ding R.
        • et al.
        Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement.
        Clin Pharmacol Ther. 2001; 70: 405-414
        View in Article
        • Food and Drug Administration
        Tetracycline FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/060704s035lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        DORYX® (doxycycline hyclate) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050795s005lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        Erythromycin ethylsuccinate FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050207s071lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        Cleocin HCl® (clindamycin hydrochloride) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/050162s092s093lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        Kenalog CREAM (triamcinolone acetonide) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/pre96/011601s036lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        CLARITIN® (loratadine) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20641s7lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        Acetaminophen FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204767s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        Motrin® (ibuprofen) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017463s105lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        Ultram ER (tramadol hydrochloride) FDA Package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021692s015lbl.pdf
        Date accessed: December 2, 2022
        View in Article

      31. Food and Drug Administration. DOLOPHINE® (methadone hydrochloride) FDA package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/006134s045lbl.pdf. Accessed September 2, 2022.

        View in Article
        • Food and Drug Administration
        ZOHYDRO® ER (hydrocodone bitartrate) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202880s020lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        OXYCONTIN® (oxycodone hydrochloride) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022272s046lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        Duragesic (fentanyl transdermal system) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/019813s081lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        BUTRANS (buprenorphine) Transdermal Patch FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021306s015s019lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        Codeine sulfate FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022402s014lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        OPANA® ER (oxymorphone hydrochloride) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021610s028lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        NUCYNTA® (tapentadol) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022304s023lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        Morphine sulfate FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022207s004lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        DILAUDID® INJECTION (hydromorphone hydrochloride) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/019034s035lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        ELIQUIS (apixaban) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        XARELTO® (rivaroxaban) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202439s017lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        SAVAYSA (edoxaban) FDA package insert.
        https://www.accessdata.fda.gov/spl/data/ddafd408-bb00-4aac-b7fb-aa2c8bb8de88/ddafd408-bb00-4aac-b7fb-aa2c8bb8de88.xml#S7.1
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        Lovenox (enoxaparin sodium injection) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020164s083lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        FRAGMIN® (dalteparin sodium) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020287s072lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        COUMADIN (warfarin sodium) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Food and Drug Administration
        ARIXTRA (fondaparinux sodium) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021345s019lbl.pdf
        Date accessed: December 2, 2022
        View in Article
        • Gambillara E.
        • Laffitte E.
        • Widmer N.
        • et al.
        Severe pustular eruption associated with imatinib and voriconazole in a patient with chronic myeloid leukemia.
        Dermatology. 2005; 211: 363-365
        View in Article
        • Food and Drug Administration
        Drug development and drug interactions | Table of substrates, inhibitors and inducers.
        https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
        Date accessed: September 2, 2022
        View in Article
        • Wang L.
        • Berger N.A.
        • Davis P.B.
        • Kaelber D.C.
        • Volkow N.D.
        • Xu R.
        COVID-19 rebound after paxlovid and molnupiravir during January–June 2022. medRxiv.
        https://www.medrxiv.org/content/10.1101/2022.06.21.22276724v1
        Date accessed: September 2, 2022
        View in Article
        • Boosman R.J.
        • de Gooijer C.J.
        • Groenland S.L.
        • et al.
        Ritonavir-boosted exposure of kinase inhibitors: an open label, cross-over pharmacokinetic proof-of-concept trial with erlotinib.
        Pharm Res. 2022; 39: 669-676
        View in Article

      52. Kabinger F, Stiller C, Schmitzová J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol 09. 2021;28:740–746.

        View in Article

      53. Atmar RL, Finch N. New perspectives on antimicrobial agents: molnupiravir and Nirmatrelvir/Ritonavir for treatment of COVID-19. Antimicrob Agents Chemother. 08 16 2022;66:e0240421.

        View in Article

      54. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 02 10 2022;386:509–520.

        View in Article
        • Zou H.X.
        • Zhang Y.F.
        • Zhong D.F.
        • et al.
        Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model.
        Acta Pharmacol Sin. 2022; 43: 1865-1874
        View in Article
        • Liu D.
        • Jiang J.
        • Zhang L.
        • et al.
        Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects.
        Cancer Chemother Pharmacol. 2014; 73: 721-727
        View in Article
        • Zhang T.
        • Zhang K.
        • Ma L.
        • et al.
        Metabolic pathway of icotinib in vitro: the differential roles of CYP3A4, CYP3A5, and CYP1A2 on potential pharmacokinetic drug-drug interaction.
        J Pharm Sci. 2018; 107: 979-983
        View in Article
        • Food and Drug Administration
        Lazertinib Korean package insert.
        https://nedrug.mfds.go.kr/pbp/CCBBB01/getItemDetail?itemSeq=202100467
        Date accessed: September 2, 2022
        View in Article

      59. ClinicalTrials.gov. A phase I/II, open-label, multicenter student to assess the safety, tolerability, pharmacokinetics and anti-tumor efficacy of DZD9008 (Sunvozertinib) in patients with advanced non-small cell lung cancer (NSCLC) with EGFR or HER2 mutation. https://clinicaltrials.gov/ct2/show/NCT03974022. Accessed September 2, 2022.

        View in Article
        • Food and Drug Administration
        ALECENSA® (alectinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208434s003lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Cleveland Clinic
        A phase 1/2. open-label, multi-center, first-in-human study of the safety, of the safety, tolerability, pharmacokinetics, and anti-tumor activity of TPX-0005 , of TPX-0005 (repotrectinib) in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1–3 rearrangements (TRIDENT-1).
        https://my.clevelandclinic.org/clinical-trials/1251-a-phase-12-open-label-multi-center-first-in-human-study-of-the-safety-tolerability-pharmacokinetics-and-anti-tumor-activity-of-tpx-0005-in-patients-with-advanced-solid-tumors-harboring-alk-ros1-or-ntrk1-3-rearrangements-trident-1
        Date accessed: September 2, 2022
        View in Article

      62. Cleveland Clinic. A single-arm, open-label, multicenter phase 2 study to evaluate the efficacy and safety of taletrectinib in patients with advanced or metastatic ROS1 positive NSCLC and other solid tumors. https://my.clevelandclinic.org/clinical-trials/1558-a-single-arm-open-label-multicenter-phase-2-study-to-evaluate-the-efficacy-and-safety-of-taletrectinib-in-patients-with-advanced-or-metastatic-ros1-positive-nsclc-and-other-solid-tumors. Accessed September 2, 2022.

        View in Article
        • Food and Drug Administration
        TEPMETKO® (tepotinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214096s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        LUMAKRAS™ (sotorasib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214665s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        NERLYNX (neratinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208051s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        MEKINIST® (trametinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s007lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        COTELLIC (cobimetinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        ZELBORAF® (vemurafenib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429s012lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        BRAFTOVI™ (encorafenib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Food and Drug Administration
        MEKTOVI® (binimetinib) package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf
        Date accessed: October 1, 2022
        View in Article
        • Food and Drug Administration
        CABOMETYX® (cabozantinib) FDA package insert.
        https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208692s003lbl.pdf
        Date accessed: September 2, 2022
        View in Article
        • Sun Y.
        • Niu W.
        • Du F.
        • et al.
        Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors.
        J Hematol Oncol. 2016; 9: 105
        View in Article
        • Zhong C.C.
        • Chen F.
        • Yang J.L.
        • et al.
        Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species.
        Acta Pharmacol Sin. 2018; 39: 1048-1063
        View in Article

      Article info

      Publication history

      Published online: December 17, 2022
      Accepted: December 15, 2022
      Received in revised form: December 12, 2022
      Received: October 6, 2022

      Footnotes

      Disclosure: The authors declare no conflict of interest and the article and data have not been previously published, and that no similar article is in press or under review elsewhere.

      Cite this article as: Anwar K, Nguyen L, Nagasaka M, Ou SHI, Chan A. Overview of drug-drug interactions between ritonavir-boosted nirmatrelvir (paxlovid) and targeted therapy and supportive care for lung cancer. JTO Clin Res Rep. 2023;4:100452.

      Identification

      DOI: https://doi.org/10.1016/j.jtocrr.2022.100452

      Copyright

      © 2022 Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.

      User license

      Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) |
      How you can reuse Information Icon
      Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)

      Permitted

      For non-commercial purposes:

      • Read, print & download
      • Redistribute or republish the final article
      • Text & data mine
      • Translate the article (private use only, not for distribution)
      • Reuse portions or extracts from the article in other works

      Not Permitted

      • Sell or re-use for commercial purposes
      • Distribute translations or adaptations of the article

      Elsevier's open access license policy

      ScienceDirect

      Access this article on ScienceDirect

      The content on this site is intended for healthcare professionals.


      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the Cookie Preference Center for this site.
      Copyright © 2023 Elsevier Inc. except certain content provided by third parties.


      RELX