Population Pharmacokinetics and Pharmacodynamics of BYL719, a Phosphoinositide 3-kinase Antagonist, in Adult Patients with Advanced Solid Malignancies

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2014 Mar 13

PMID 24617631

Citations 13

Authors

Stefan S De Buck

Annamaria Jakab

Markus Boehm

Douglas Bootle

Dejan Juric

Cornelia Quadt

Timothy K Goggin

Affiliations

Soon will be listed here.

Abstract

Aims: The aim was to characterize the population pharmacokinetics of BYL719 in cancer patients and assess the time course of tumour response in relation to drug exposure and dosing schedule.

Methods: Plasma samples and longitudinal tumour size measurements were collected from 60 patients with advanced solid malignancies who received oral BYL719 once daily (30-450 mg) or twice daily at 120 mg or 200 mg. Non-linear mixed effect modelling was employed to develop the population pharmacokinetic and pharmacodynamic model.

Results: The pharmacokinetics were best described by a one compartment disposition model and transit compartments accounting for the lag time in absorption. The typical population oral clearance and volume of distribution estimates with their between-subject variability (BSV) were 10 l h(-1) (BSV 26%) and 108 l (BSV 28%), respectively. The estimated optimal number of transit compartments was 8.1, with a mean transit time to the absorption compartment of 1.28 h (BSV 32%). The between-occasion variability in the rate and extent of absorption was 46% and 26%, respectively. Tumour growth was modelled using a turnover model characterized by a zero order growth rate of 0.581 cm week(1) and a first order death rate of 0.0123 week(-1) . BYL719 inhibited tumour growth with an IC50 of 100 ng ml(-1) (BSV 154%). Model-based predictions showed potential for additional anti-tumour activity of twice daily dosing at total daily dose below 400 mg, but a loss of efficacy if administered less frequently than once daily.

Conclusions: The proposed model provides a valuable approach for planning future clinical studies and for designing optimized dosing regimens with BYL719.

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