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Ref Type Journal Article
PMID (24617631)
Authors De Buck SS, Jakab A, Boehm M, Bootle D, Juric D, Quadt C, Goggin TK
Title Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies.
Journal British journal of clinical pharmacology
Vol 78
Issue 3
Date 2014 Sep
Abstract Text 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.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.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.The proposed model provides a valuable approach for planning future clinical studies and for designing optimized dosing regimens with BYL719.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable Alpelisib Phase I Actionable In a Phase I clinical trial, Alpelisib (BYL719) demonstrated safety and some efficacy in patients with advanced solid tumors (PMID: 24617631). 24617631