Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer

Abstract

AIMSLenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans. METHODSThis population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC. RESULTSThe final pooled dataset included data from 779 subjects receiving 3.2-32 mg oral lenvatinib, mainly once daily as tablets or capsules. Lenvatinib PK was best described by a three-compartment model with linear elimination. Lenvatinib absorption was best described by simultaneous first-and zero-order absorption. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h À1 [percent coefficient of variation (%CV) 25.5], and was independent of dose and time. The relative bioavailability of lenvatinib in capsule form was 90% vs. tablets (%CV 30.2). The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liver-function markers [alkaline phosphatase (À11.7%) and albumin (À6.3%)] and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (À7.8%) on lenvatinib CL/F. Lenvatinib PK was unaffected by pH-elevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function. CONCLUSIONSThe significant effects of several covariates on lenvatinib PK variability were small in magnitude, and therefore were not considered clinically relevant, or to warrant any dose adjustment. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacokinetics of lenvatinib have previously been studied only in individual clinical trials with limited sample sizes, or in targeted pharmacokinetic studies of special populations (e.g. subjects with renal or hepatic impairment). WHAT THIS STUDY ADD• The first population pharmacokinetic analysis for lenvatinib provides crucial insight into the intrinsic and extrinsic factors affecting lenvatinib pharmacokinetics.• The study provides useful information on the interaction of lenvatinib with pH-elevating agents commonly used by cancer patients, based on clinical trial data and not as a prospectively designed drug-drug-interaction study.

Treatment‐emergent hypertension and efficacy in the phase 3 Study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT)

“…A pharmacokinetic model was developed with pooled data from studies of healthy patients, patients with solid tumors, and patients with thyroid cancer (including the SELECT study). Details of the pharmacokinetic model have been reported previously . The pharmacokinetic analysis also examined the relation between lenvatinib exposure and OS in the SELECT trial as well as the relation between lenvatinib exposure and the occurrence of HTN with pooled data from 3 studies of patients with RR‐DTC.…”

“…Details of the pharmacokinetic model have been reported previously. 10 The pharmacokinetic analysis also examined the relation between lenvatinib exposure and OS in the SELECT trial as well as the relation between lenvatinib exposure and the occurrence of HTN with pooled data from 3 studies of patients with RR-DTC.…”

Exposure–response analysis and simulation of lenvatinib safety and efficacy in patients with radioiodine-refractory differentiated thyroid cancer

“…The patient characteristics, data set, and final population PK model are described in detail in this previous publication [7]. As noted in Gupta et al [7], all patients had provided written informed consent.…”

Lenvatinib and its Use in the Treatment of Unresectable Hepatocellular Carcinoma

“…Peak plasma concentrations were reached at 1.6 hours following a single dose of 24mg with a terminal half-life of 34.5 hours [31]. Lenvatinib is metabolised in several ways including via cytochrome P450 3A, aldehyde oxidase and conjugation with glutathione [32,33]. 2.5% is excreted unchanged and the probability of drug-drug interaction is low [34].…”