De Buck, Stefan, Jakab, Annamaria, Boehm, Markus, Bootle, Douglas, Quadt, Cornelia, Goggin, Timothy Kieran and Juric, Dejan (2014) Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies. British Journal of Clinical Pharmacology.

Abstract

Aims: To characterize the population pharmacokinetics of BYL719 in adult cancer patients and assess the time course of tumor response in relation to drug exposure and dosing schedule
Methods: Plasma samples and longitudinal tumor 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 modeling was employed to develop the population pharmacokinetic and pharmacodynamic model. Goodness of model fit was assessed according to graphical and statistical criteria.
Results: Pharmacokinetics was 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 (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 hours (BSV 32%). The between-occasion variability in the rate and extent of absorption was 46% and 26%, respectively. Tumor growth was modeled 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 tumor growth with an IC50 of 100 ng/ml (BSV 154%). Model-based predictions showed potential for additional anti-tumor 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.

Item Type:	Article
Additional Information:	Abstract: 250 words; Manuscript: 8994 words; References: 33; Figures: 8; Tables: 7
Keywords:	phosphoinositide 3-kinase, cancer, BYL719, population pharmacokinetics, transit compartment, tumor turnover, response
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/10096