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Open Access 01-04-2021 | NSCLC | Original Article

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

Authors: Felipe K. Hurtado, Filippo de Braud, Javier De Castro Carpeño, Maria Jose de Miguel Luken, Ding Wang, Jeffrey Scott, Yvonne Y. Lau, Tracey McCulloch, Morten Mau-Sorensen

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2021

Abstract

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.

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Title: 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
Authors: Felipe K. Hurtado
Filippo de Braud
Javier De Castro Carpeño
Maria Jose de Miguel Luken
Ding Wang
Jeffrey Scott
Yvonne Y. Lau
Tracey McCulloch
Morten Mau-Sorensen
Publication date: 01-04-2021
Publisher: Springer Berlin Heidelberg
Keywords: NSCLC
Pharmacokinetics
NSCLC
Warfarin
Ceritinib
Midazolam
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2021
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04180-3

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