An Open-Label Phase 1 Study to Determine the Effect of Lenvatinib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Patients with Advanced Solid Tumors

Robert Shumaker, Min Ren, Jagadeesh Aluri, Corina E Dutcus, Christian Rance, Cixin He, Robert Shumaker, Min Ren, Jagadeesh Aluri, Corina E Dutcus, Christian Rance, Cixin He

Abstract

Background and objective: Lenvatinib is a multikinase inhibitor that inhibits enzyme activity but induces gene expression of cytochrome P450 3A4 (CYP3A4), an important enzyme for drug metabolism. We evaluated the impact of lenvatinib on CYP3A4 using midazolam as a probe substrate in patients with advanced solid tumors. The primary objective was to determine the pharmacokinetic effects of lenvatinib on midazolam, and the secondary objective was to assess the safety of lenvatinib.

Methods: This multicenter, open-label, nonrandomized, phase 1 study involved patients with advanced cancer that progressed after treatment with approved therapies or for which no standard therapies were available.

Results: Compared with baseline, coadministration of lenvatinib decreased the geometric mean ratio of the area under the concentration-time curve for midazolam on day 1 to 0.914 (90% confidence interval [CI] 0.850-0.983) but increased it on day 14 to 1.148 (90% CI 0.938-1.404). Coadministration of lenvatinib also decreased the geometric mean ratio of the maximum observed concentration for midazolam on day 1 to 0.862 (90% CI 0.753-0.988) but increased it on day 14 to 1.027 (90% CI 0.852-1.238). There was little change in the terminal elimination phase half-life of midazolam when administered with lenvatinib. The most common treatment-related adverse events were hypertension (20.0%), fatigue (16.7%), and diarrhea (10.0%).

Conclusions: Coadministration of lenvatinib had no clinically relevant effect on the pharmacokinetics of midazolam, a CYP3A4 substrate. The adverse events were consistent with the known safety profile of lenvatinib, and no new safety concerns were identified. CLINICALTRIALS.

Gov identifier: NCT02686164.

Conflict of interest statement

Robert Shumaker is a former employee of Eisai Inc., Woodcliff Lake, NJ, USA. Min Ren, Jagadeesh Aluri, Corina Dutcus, Christian Rance and Cixin He are currently employed by Eisai Inc., Woodcliff Lake, NJ, USA.

Figures

Fig. 1
Fig. 1
Treatment schedule. aThe treatment phase for this pharmacokinetic analysis spanned day −3 to day 14. bThe extension phase started on day 15 for all patients remaining in the study
Fig. 2
Fig. 2
Patient disposition
Fig. 3
Fig. 3
Forest plot of drug–drug interactions of midazolam and 1′-OH midazolam coadministered with single and multiple doses of lenvatinib in the pharmacokinetic analysis set (n = 29). D −3 midazolam only, D1 1 dose of lenvatinib and midazolam, D14 multiple doses of lenvatinib and 1 dose of midazolam, AUC0–24 area under the concentration–time curve from time 0 to 24 h after midazolam dose, D# day number, Cmax maximum observed (peak) drug concentration
Fig. 4
Fig. 4
Semi-log plot of mean plasma concentration–time profile of midazolam (a) and 1′-OH midazolam (b) with and without lenvatinib in the pharmacokinetic analysis (n = 29) set. D −3 day −3 (midazolam dose only), D1 day 1 (1 dose of lenvatinib and midazolam), D14 day 14 (multiple doses of lenvatinib and 1 dose of midazolam)

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