Nonmem covariate analysis with placebo subjects

Lenvatinib has been evaluated extensively in phase 1 studies both in healthy subjects and patients with solid tumours 6, 7, 8, 9, 10, 11, 12, 13, as well as in phase 2 studies in patients with various types of thyroid cancer (Eisai data on file) 14.ДЇollowing oral administration in humans, lenvatinib is absorbed rapidly, with the observed time for the maximum concentration to occur ( t max) typically ranging between 1 h and 4 h 15. The targeting of multiple angiogenic pathways may circumvent the compensatory mechanisms that are upregulated when only a single angiogenic pathway is inhibited 5. Lenvatinib is an oral multikinase inhibitor of vascular endothelial growth factor receptor 1вЂ“3, fibroblast growth factor receptor 1вЂ“4, plateletвЂђderived growth factor receptor О±, ret protoвЂђoncogene and vвЂђkit HardyвЂ“Zuckerman 4 feline sarcoma viral oncogene homologue signalling pathways 1, 2, 3, 4. Lenvatinib PK was unaffected by pHвЂђelevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function. The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liverвЂђfunction markers and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (в€’7.8%) on lenvatinib CL/F. The relative bioavailability of lenvatinib in capsule form was 90% vs. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h в€’1, and was independent of dose and time.

Lenvatinib absorption was best described by simultaneous firstвЂђ and zeroвЂђorder absorption.

Lenvatinib PK was best described by a threeвЂђcompartment model with linear elimination. The final pooled dataset included data from 779 subjects receiving 3.2вЂ“32 mg oral lenvatinib, mainly once daily as tablets or capsules.

Nonmem covariate analysis with placebo subjects