Population Pharmacokinetic Modeling of Lucitanib in Patients with Advanced Cancer
Mingxiang Liao1, Jie Zhou2, Kenton Wride1
1Clovis Oncology, Inc., 5500 Flatiron Pkwy, Boulder, CO, 80301, USA.
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.
Insights
A population pharmacokinetics (PopPK) model was developed for lucitanib in advanced cancer patients. Body weight influenced variability, supporting a safety-based dose-titration strategy for optimal drug exposure.
Area of Science:
- Pharmacology
- Oncology
- Clinical Pharmacy
Background:
- Lucitanib is an oral, potent, selective inhibitor targeting VEGFR, FGFR, and PDGFR.
- It is investigated for advanced cancers.
Purpose of the Study:
- To develop a population pharmacokinetics (PopPK) model for lucitanib.
- To characterize lucitanib's pharmacokinetic profile in patients with advanced cancers.
Main Methods:
- PopPK analysis utilized intensive and sparse data from 403 patients across 5 Phase 1/2 studies.
- Lucitanib was administered in daily doses of 5-30 mg via film-coated tablets or hard gelatin capsules.
Main Results:
- A 2-compartment model with zero-order release, first-order absorption, and first-order elimination best described lucitanib pharmacokinetics.
- Body weight was a significant covariate, explaining some between-subject variability.
- No significant impact on pharmacokinetics was observed for demographics, tumor type, CYP/P-gp interactions, renal/hepatic impairment, or proton pump inhibitors.
Conclusions:
- The developed PopPK model adequately describes lucitanib pharmacokinetics.
- High inter-individual variability supports the current safety-based dose-titration strategy to optimize lucitanib therapy.
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