A randomized, three-treatment, three-period, six-sequence-crossover, single-center, bioequivalence study to evaluate the impact of different 10-mg crystalline forms on the pharmacokinetics of lenvatinib in healthy volunteers

Lee, Lucy; D’Angelo, Pina; Verbel, David; Martinez, Gresel; Aluri, Jagadeesh; Brimhall, Darin

doi:10.5414/cp202216

Cited by 2 publications

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“…The current analysis was based on pooled data collected from eight phase 1 studies of lenvatinib in healthy subjects (Eisai data on file) , four phase 1 studies of lenvatinib in patients with solid tumours (Eisai data on file) , two phase 2 studies of lenvatinib in patients with thyroid cancers and the phase 3 SELECT trial of patients with RR‐DTC . All patients signed informed consent forms for participation in the respective trials, which were conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and local regulations, and approved by the independent review boards of each participating centre.…”

Section: Methodsmentioning

confidence: 99%

“…The targeting of multiple angiogenic pathways may circumvent the compensatory mechanisms that are upregulated when only a single angiogenic pathway is inhibited . Lenvatinib has been evaluated extensively in phase 1 studies both in healthy subjects and patients with solid tumours , as well as in phase 2 studies in patients with various types of thyroid cancer (Eisai data on file) .…”

Section: Introductionmentioning

confidence: 99%

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

Gupta

Jarząb

Capdevila

et al. 2016

Brit J Clinical Pharma

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Gupta

Jarząb

Capdevila

et al. 2016

Brit J Clinical Pharma

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Clinical Pharmacokinetic and Pharmacodynamic Profile of Lenvatinib, an Orally Active, Small-Molecule, Multitargeted Tyrosine Kinase Inhibitor

Hussein

Mizuo

Hayato

et al. 2017

Eur J Drug Metab Pharmacokinet

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Lenvatinib is a multikinase inhibitor that targets vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor-alpha, and RET and KIT proto-oncogenes. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer in the United States (US), European Union (EU), Canada, Japan, and Switzerland. It is also approved in combination with everolimus for the treatment of advanced renal cell carcinoma following ≥1 VEGF-targeted treatment in the US and EU. In addition, lenvatinib is under investigation for the treatment of hepatocellular carcinoma. As lenvatinib becomes more widely available, a better understanding of its pharmacokinetic profile has become increasingly important. Following oral administration, lenvatinib is absorbed rapidly and is metabolized extensively prior to excretion. This metabolism is mediated by multiple pathways, and several metabolites of lenvatinib have been identified. The effect of food intake on lenvatinib exposure has also been studied and was found to not significantly influence overall exposure to the drug. Exposure to lenvatinib is increased in patients with severe hepatic impairment, indicating that dose reduction must be considered for those patients. The findings summarized here indicate that the clinical pharmacokinetic and pharmacodynamic profile for lenvatinib are predictable, with a dose-independent absorption and elimination profile that supports once-daily administration, and has minimal effects due to mild or moderate renal or hepatic impairment or drug interactions.

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A randomized, three-treatment, three-period, six-sequence-crossover, single-center, bioequivalence study to evaluate the impact of different 10-mg crystalline forms on the pharmacokinetics of lenvatinib in healthy volunteers

Abstract: For both comparisons, the 90% CIs of the test/reference ratios were within the regulatory acceptance range (80-125%), suggesting that both test formulations (low Cform and high C-form) were bioequivalent to the reference formulation for Cmax, AUC0-t, and AUC0-∞.

Cited by 2 publications

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

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

Clinical Pharmacokinetic and Pharmacodynamic Profile of Lenvatinib, an Orally Active, Small-Molecule, Multitargeted Tyrosine Kinase Inhibitor

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