Population Pharmacokinetic Modeling of Lucitanib in Patients with Advanced Cancer

Abstract

Background: Lucitanib is an oral, potent, selective inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptors 1‒3, fibroblast growth factor receptors 1‒3, and platelet-derived growth factor receptors alpha/beta.

Objective: We aimed to develop a population pharmacokinetics (PopPK) model for lucitanib in patients with advanced cancers.

Methods: PopPK analyses were based on intensive and sparse oral pharmacokinetic data from 5 phase 1/2 clinical studies of lucitanib in a total of 403 patients with advanced cancers. Lucitanib was administered at 5‒30 mg daily doses as 1 of 2 immediate-release oral formulations: a film-coated tablet or a hard gelatin capsule.

Results: Lucitanib pharmacokinetics were best described by a 2-compartment model with zero-order release into the dosing compartment, followed by first-order absorption and first-order elimination. Large between-subject pharmacokinetic variability was partially explained by body weight. No effects of demographics or tumor type on lucitanib pharmacokinetics were observed. The model suggested that the formulation impacted release duration (tablet, 0.243 h; capsule, 0.814 h), but the effect was not considered clinically meaningful. No statistically significant effects were detected for concomitant cytochrome P450 (CYP) 3A4 inhibitors or inducers, CYP2C8 or P-glycoprotein inhibitors, serum albumin, mild/moderate renal impairment, or mild hepatic impairment. Concomitant proton pump inhibitors had no clinically significant effect on lucitanib absorption.

Conclusions: The PopPK model adequately described lucitanib pharmacokinetics. High between-subject pharmacokinetic variability supports a safety-based dose-titration strategy currently being used in an ongoing clinical study of lucitanib to optimize drug exposure and clinical benefit.

Trial registration: ClinicalTrials.gov Identifier: NCT01283945, NCT02053636, ISRCTN23201971, NCT02202746, NCT02109016.

Fig. 1

PopPK model structure. The pharmacokinetics of lucitanib were described by a 2-compartment linear model with a zero-order release into the dosing compartment, followed by first-order absorption and first-order elimination. Volume (Vc, Vp) and clearance (Q, CL) terms were proportional to Weight^exponent (a power model of weight with exponents fixed to 1 for volume terms and 0.75 for clearance terms). Duration of release from the tablet formulation (0.243 h) differed from the capsule (0.814 h). CL clearance, Ka first-order absorption rate constant, PopPK population pharmacokinetics, Q intercompartmental clearance, Vc central volume, Vp peripheral volume

Fig. 2

Goodness-of-fit plots for the final lucitanib PopPK model. a Population prediction (ETA = 0) versus observed; b individual prediction (ETA ≠ 0) versus observed; c prediction versus conditional weighted residual; and d time versus conditional weighted residual. Blue lines indicate smoothed means (locally estimated scatterplot smoothing, LOESS [34]). Black trend lines indicate lines of unity (intercept = 0, slope = 1). Observations (concentrations or residuals, black dots) from the same individual are connected by black lines. ETA random effects values for pharmacokinetic parameters, PopPK population pharmacokinetics

Fig. 3

Visual predictive check for the final lucitanib PopPK model: time since first dose versus lucitanib concentration. PopPK population pharmacokinetics

Fig. 4

Conditional weighted residuals by formulation. Black horizontal lines represent median values, and boxes correspond to the ranges of the first and third quartiles. Upper and lower whiskers extend from the box to the largest or smallest value, respectively, within 1.5 times the interquartile range. Observations outside the whisker range are represented as dots

Fig. 5

Post hoc estimates of BSV of Ka by formulation. Black horizontal lines represent median values, and boxes correspond to the ranges of the first and third quartiles. Upper and lower whiskers extend from the box to the largest or smallest value, respectively, within 1.5 times the interquartile range. Observations outside the whisker range are represented as dots. BSV between-subject variability, ETA random effects values for pharmacokinetic parameters, Ka first-order absorption rate constant

Fig. 6

Post hoc estimates of BSV of CL/F by formulation. Black horizontal lines represent median values, and boxes correspond to the ranges of the first and third quartiles. Upper and lower whiskers extend from the box to the largest or smallest value, respectively, within 1.5 times the interquartile range. Observations outside the whisker range are represented as dots. BSV between-subject variability, CL/F apparent clearance, ETA random effects values for pharmacokinetic parameters