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

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.

SUBMITTER: De Buck SS

PROVIDER: S-EPMC4243905 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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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 S SS Jakab Annamaria A Boehm Markus M Bootle Douglas D Juric Dejan D Quadt Cornelia C Goggin Timothy K TK

British journal of clinical pharmacology 20140901 3

<h4>Aims</h4>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.<h4>Methods</h4>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 pharmaco ...[more]

PMID: 24617631

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Project description:BACKGROUND:Excessive neutrophil presence and activation is important in a number of acute and chronic inflammatory diseases. The CXCR2 chemokine receptor is important in controlling the extravasation and activation of neutrophils. Selective antagonism of the CXCR2 receptor is a potential approach to reducing neutrophil migration and activation. Danirixin, is a small molecule, CXCR2 antagonist being evaluated as a potential anti-inflammatory medicine. METHODS:(1) First time in human (FTIH) double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics, and pharmacodynamics of single ascending and repeat oral doses of danirixin in healthy male subjects; (2) single-dose study of age, gender, food, and proton-pump inhibitor effects on the pharmacokinetics of danirixin in healthy adult subjects; and placebo-controlled study of the pharmacokinetics of danirixin in healthy elderly subjects. RESULTS:There were no serious adverse events and no adverse events considered to be of clinical relevance. There were no withdrawals due to adverse events. Systemic exposure following single doses of danirixin 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg increased with increasing dose. Engagement of pharmacology was demonstrated as inhibition of ex-vivo CXCL1-induced CD11b expression on peripheral blood neutrophils when compared to placebo (approximately 50% for 50 mg and 100 mg danirixin, and 72% at 200 mg). There was a 37% decrease in Cmax and a 16% decrease in AUC (0-?) following administration of danirixin in the presence of food. Cmax also decreased by 65% when danirixin 100 mg was administered following omeprazole 40 mg once daily for 5 days. The AUC (0-?) and Cmax were 50% lower in elderly subjects compared with younger subjects. CONCLUSION:The dose-dependent inhibition of agonist-induced neutrophil activation following single and repeated once daily oral administration of danirixin suggests that this CXCR2 antagonist may have benefit in neutrophil-predominant inflammatory diseases. Co-administration with food, gastric acid reducing agents, and variable exposure in the elderly have important clinical implications that need to be taken into consideration in subsequent clinical evaluations. TRIAL REGISTRATION:ClinicalTrials.gov identifiers: NCT01209052 and NCT01209104.

Dataset Information

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

Publications

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

Similar Datasets

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