Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug-drug interaction study in patients with ALK + advanced tumors.

Autor: Hurtado FK; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. felipe.kellermann_hurtado@novartis.com., de Braud F; Fondazione IRCCS-Istituto Nazionale Dei Tumori, Milano, Italy., De Castro Carpeño J; Medical Oncology Department, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain., de Miguel Luken MJ; CIOCC-Grupo Hospitalario de Madrid, Hosp. de Sanchinarro, Madrid, Spain., Wang D; Henry Ford Cancer Institute, Detroit, MI, USA., Scott J; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA., Lau YY; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA., McCulloch T; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA., Mau-Sorensen M; Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2021 Apr; Vol. 87 (4), pp. 475-486. Date of Electronic Publication: 2021 Jan 04.
DOI: 10.1007/s00280-020-04180-3
Abstrakt: Purpose: Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively.
Methods: This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily.
Results: Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC.
Conclusion: Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.
Databáze: MEDLINE
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