Abstract 5373
Background
Tepotinib is an oral, highly selective MET inhibitor being investigated in MET-driven solid tumors. Cancer patients often receive co-medications, many of which are subject to cytochrome P450 3A (CYP3A) or P-glycoprotein (P-gp)-dependent pharmacokinetics.
The potential of tepotinib to alter the exposure to such drugs was investigated in two clinical drug-drug interaction (DDI) trials.
Methods
The effect of multiple doses of the RP2D of tepotinib (500 mg QD) on the exposure of single doses of the sensitive CYP3A4 substrate midazolam and the sensitive P-gp substrate dabigatran etexilate were tested in healthy subjects, using randomized single-sequence two-period cross-over designs. The primary endpoints were Cmax and AUC for the respective probe drugs; their corresponding ratios of the geometric least-squares means (GLSM) (90% CI) in the presence/absence of tepotinib were reported. Additional PK measures, safety and tolerability were also evaluated.
Results
Most participants were male (12/12 midazolam; 19/20 dabigatran etexilate); mean age 34 years (range 19–44). There was no increase in midazolam exposure with co-administration of tepotinib (Table), suggesting that no effect on the metabolism of CYP3A is to be expected. Co-administration of tepotinib led to a 39–45% increase in dabigatran etexilate exposure. No clinically relevant effects on laboratory values, vital signs or ECG parameters were observed or reported as an AE.Table:
480P
CYP3A substrate (Midazolam) Ratio of GLSM% (90% CI) | P-gp substrate (Dabigratan) Ratio of GLSM% (90% CI) | |
---|---|---|
Tepotinib + Midazolam / Midazolam | Tepotinib + Dabigatran etexilate / Dabigatran etexilate | |
AUC0-t | 1.01 (0.89; 1.15) | 1.51 (1.27; 1.80) |
AUC0-∞ | 1.01 (0.89; 1.15) | 1.45 (1.23; 1.70) |
Cmax | 1.04 (0.87;1.24) | 1.38 (1.22; 1.58) |
AUC0-t, area under the plasma concentration-time curve from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification;
AUC0-∞, area under the plasma concentration-time curve from time zero (= dosing time) extrapolated to infinity; Cmax, maximum plasma concentration observed; GLSM, geometric least-squares mean.
Conclusions
After multiple doses of tepotinib at the RP2D (500 mg QD), there was no relevant exposure increase of the sensitive CYP3A substrate midazolam, and a < 2-fold mean exposure increase of the sensitive P-gp substrate dabigatran etexilate, indicating that tepotinib is a weak P-gp inhibitor. Tepotinib was considered safe and well tolerated in these studies of healthy volunteers. In summary, the potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the intended posology is considered low.
Clinical trial identification
NCT03492437 and NCT03628339.
Editorial acknowledgement
Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Sandra Cuscó, PhD of Bioscript Group (Macclesfield, UK).
Legal entity responsible for the study
Merck Healthcare KGaA.
Funding
Merck Healthcare KGaA.
Disclosure
Ö. Yalkinoglu: Full / Part-time employment: Merck Healthcare KGaA. A. Becker: Full / Part-time employment: Merck Healthcare KGaA. A. Krebs-Brown: Full / Part-time employment: Merck Healthcare KGaA. R. Strotmann: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.
Resources from the same session
4321 - Health-related quality of life of advanced melanoma survivors treated with CTLA-4 immune checkpoint inhibition: a matched cohort study
Presenter: Annelies Boekhout
Session: Poster Display session 1
Resources:
Abstract
779 - Capecitabine vs Cisplatin along with concurrent radiotherapy in the treatment of inoperable lower esophageal cancers focusing on TWISTT score and QOL
Presenter: Goutham Anugu
Session: Poster Display session 1
Resources:
Abstract
5914 - Cancer, Mental Health and End Life Simulation (CAMhELS): A novel effectiveness evaluation.
Presenter: Asanga Fernando
Session: Poster Display session 1
Resources:
Abstract
2597 - Cancer patients’ expectations and understanding about their disease
Presenter: Mónica Pinho
Session: Poster Display session 1
Resources:
Abstract
5187 - Impact of patients’ death on oncologists and coping strategies: An online survey
Presenter: Soumaya Labidi
Session: Poster Display session 1
Resources:
Abstract
4579 - Clinical benefit from late lines of therapy offered to patients treated in a tertiary referral centre
Presenter: Andrea Sbrana
Session: Poster Display session 1
Resources:
Abstract
5058 - Preparedness for caregiving in caregivers of cancer patients
Presenter: Hatice Yakar
Session: Poster Display session 1
Resources:
Abstract
5917 - Oncologic Emergency Medicine in the real world: A survey and proposal for improvement
Presenter: Carintia Dorta Pérez
Session: Poster Display session 1
Resources:
Abstract
4077 - The Reality of Critical Cancer Patients in a Polyvalent Intensive Care Unit
Presenter: Tiago Filipe Da Cruz Tomas
Session: Poster Display session 1
Resources:
Abstract
1728 - A phase III trial evaluating olanzapine 5 mg for the prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin: J-FORCE Study
Presenter: Hironobu Hashimoto
Session: Poster Display session 1
Resources:
Abstract