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Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies

De Buck, Stefan and Jakab, Annamaria and Boehm, Markus and Bootle, Douglas and Quadt, Cornelia and 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

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