Stefan S.S. De Buck, Annamaria Jakab, Douglas Bootle, Markus Boehm, Cornelia Quadt and Timothy K Goggin
Oncology Clinical Pharmacology, Novartis, Basel
Objectives: To characterized the dose concentration effect relationship of BYL719, a phosphoinositide 3-kinase (PI3K) antagonist, in patients with advance solid malignancies.
Methods: The scope of this study was to develop a population pharmacokinetic and pharmacodynamic (PK/PD) model using the data from an ascending multiple dose, "proof of concept study", phase 1 clinical study. The model was used to assess the between-subject (BSV) and between-occasion (BOV) variability in drug exposure. The relationship between drug exposure and tumour response was also explored and schedule dependence assessed. Serial PK 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 (120-200 mg). BYL719 was measured in plasma using an HPLC-MS/MS method and the sum of the longest diameter of target lesions was measured using CT or MRI scans. Goodness of fit was assessed by; classical diagnostic plots, visual predictive checks, bootstrap procedure, and precision of parameters throughout the model building process.
Results: The PK of BYL719 was best described by an open one-compartment disposition model with transit compartments accounting for the lag in absorption. The apparent clearance and volume of distribution of BYL719 in the population were 10 L/h and 108 L, with BSV of 26% and 28 % respectively. The estimated optimal number of transit compartment was 8.1, with mean transit time (MTT) to the absorption compartment of 1.28 h (BSV 32%). Considerable BOV in the rate (MTT) and relative extent of absorption (Frel) was found (46% and 26% respectively). Tumour growth was modeled using a turnover model with a zero order growth rate (Kgrowth, 0.581 cm/week) and a first order death rate (Kdeg, 0.0123 1/week). BYL719 inhibited growth with an IC50 of 100 ng/mL (BSV, 154%). Based on stochastic simulation of fully adherent patients, administered 400 mg once daily (the defined MTD based on an adaptive Bayesian logistic regression model with overdose control), the fraction of patients experiencing stable disease or a partial response at 20 weeks, according to the RECIST criteria was 78% and 9 % respectively. Assessment of schedule dependence indicated only a very limited difference between once or twice daily administrations of a total daily dose of 400 mg but there was an advantage of twice daily administration of the same total dose at lower doses. A considerable loss of benefit was seen already at a dosing rate of 800 mg every other day.
Conclusions: The good pharmacokinetic properties and evidence of a concentration effect relationship supports the further development of this potential therapeutic. The MTD of 400 mg given once daily seems to be an appropiate starting dose. In patients in whom mechanism based tolerability appears upon chronic dosing, a twice daily dosing rate should be considered. For example, based on the results of simulations, the administration of 100 mg given twice daily, resulted in a typical response 51 % greater than 200 mg given once daily.
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Reference: PAGE 22 (2013) Abstr 2662 [www.page-meeting.org/?abstract=2662]
Poster: Oncology