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Clinical Trial
. 2025 Jul;18(7):e70273.
doi: 10.1111/cts.70273.

Sensitivity of Tepotinib to Inhibitors or Inducers of CYP3A4 and P-Gp: Drug Interaction Studies and Physiologically-Based Pharmacokinetic Analysis

Rainer Strotmann  1 , Christian Lüpfert  1 , Axel Krebs-Brown  1 , Alice Ke  2 , Matthias Boedding  1 , Jürgen Heuer  3 , Karen Rowland Yeo  2 , Lisa Benincosa  4 , Karthik Venkatakrishnan  4
Affiliations
Clinical Trial

Sensitivity of Tepotinib to Inhibitors or Inducers of CYP3A4 and P-Gp: Drug Interaction Studies and Physiologically-Based Pharmacokinetic Analysis

Rainer Strotmann et al. Clin Transl Sci. 2025 Jul.

Abstract

Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. This work aimed to investigate the potential for drug-drug interactions with strong inhibitors and inducers of both cytochrome P450 (CYP) 3A4/5 and P-glycoprotein (P-gp) with tepotinib. Two clinical studies were conducted to investigate the effect of the strong CYP3A4/P-gp inhibitor itraconazole (200 mg once daily) (NCT05203822) and the strong CYP3A4/P-gp inducer carbamazepine (titrated to 300 mg twice daily) (NCT05213481) on the pharmacokinetics of single dose tepotinib 500 mg (450 mg active moiety) in healthy participants. An investigational physiologically-based pharmacokinetic model, developed leveraging mass balance data, was used to evaluate the mechanisms underlying these interactions. Itraconazole increased tepotinib area under the curve extrapolated to infinity (AUC0-∞) by 22% (geometric mean ratio [GMR] 122.35%; 90% confidence intervals [CIs] 111.48%, 134.29%), but had no effect on tepotinib Cmax (GMR 101.53%, 90% CI: 94.00%, 109.67%). Carbamazepine decreased tepotinib AUC0-∞ by 35% (GMR 65.15%, 90% CI: 59.80%, 70.88%) and Cmax by 11% (GMR 89.31%, 90% CI: 83.43%, 95.60%). None of these changes were considered to be clinically relevant. Single doses of tepotinib were considered safe and well tolerated in both studies. The observed pharmacokinetic interactions were consistent with a low (~17%) contribution of CYP3A4 to tepotinib metabolism without a relevant role for P-gp mediated biliary secretion. The potential of tepotinib to be a victim of modulators of both CYP3A4 and P-gp at the intended posology is considered low.

Keywords: CYP; cancers; clinical trials; drug–drug interactions; induction; inhibitors; pharmacokinetics; phase I; physiology‐based pharmacokinetics; transporters.

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Conflict of interest statement

All authors are either employees of the healthcare business of Merck KGaA, Darmstadt, Germany, who funded the research, or employees of organizations who received funding from the healthcare business of Merck KGaA, Darmstadt, Germany and may hold stock.

Figures

FIGURE 1
FIGURE 1
Study design. BID, twice daily; F/U, follow‐up visit; PK, pharmacokinetics; PK sampling: Pre‐dose (diamonds), rich sampling (boxes). Arrows: Study drug administration. Safety assessments were carried out throughout the residential periods, and at other visits until the end of study visit.
FIGURE 2
FIGURE 2
Arithmetic mean (± standard deviation for linear plot) tepotinib plasma concentration‐time profiles for tepotinib administered alone and in the presence of itraconazole. The horizontal line indicates the lower limit of quantification.
FIGURE 3
FIGURE 3
Arithmetic mean (± standard deviation for linear plot) tepotinib plasma concentration‐time profiles for tepotinib administered alone and in the presence of carbamazepine. The horizontal line indicates the lower limit of quantification.
FIGURE 4
FIGURE 4
Tepotinib PBPK modeling. Panels A and B present simulated mean plasma concentration profiles and 90% prediction intervals (solid lines and shading) and mean observed plasma concentrations (dots) from Study 1 (A, N = 17) and Study 2 (B, N = 18), respectively. (Panel C) presents simulated geometric mean ratios (GMR) with 90% CI (N = 400) for AUC0‐∞ and C max (itraconazole coadministration) for different f mCYP3A4, and with and without contribution of hepatic P‐gp to elimination and observed GMR with 90% CI from Study 1 (N = 17). AUC, area under the curve; CI, confidence interval; C max, maximal plasma concentration; f mCYP3A4, fraction metabolized by CYP3A4; GMR, geometric mean ratio; PBPK, physiologically‐based pharmacokinetic.
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