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.

Keywords: BYL719; RECIST; cancer; phosphoinositide 3-kinase; population pharmacokinetics; transit compartment.

Figure 1

Population PK model structure of the BYL719. (A) transit model and (B) t_lag model. K_tr is the first order transit transfer rate constant, K_a the first order absorption rate constant, N the total number of transit compartments, V the volume of distribution, CL the oral clearance and t_lag the absorption lag time. The absorption and central compartment correspond to respectively A_a and A_c

Figure 2

Median plasma concentration–time profile of BYL719 after (A) a single dose administration and (B) 1 month of once daily dosing. () 30 mg once daily, () 60 mg once daily, () 90 mg once daily, () 180 mg once daily, () 270 mg once daily, () 400 mg once daily, () 450 mg once daily

Figure 3

Goodness of fit plots for the population PK transit model. (A) Plot of the population-predicted vs. observed BYL719 plasma concentration. (B) Plot of individual-predicted vs. observed BYL719 plasma concentration. (C) Plot of the conditional weighted residual error (CWRES) vs. time. (D) Plot of the conditional weighted residual error (CWRES) vs. population predicted BYL719 plasma concentration. The solid line in panel A and B is the line of identity (observed=predicted)

Figure 4

Goodness of fit plots for the PK–PD model describing the longitudinal data of change in sum of tumour diameter. (A) Plot of the population-predicted vs. observed sum of tumour diameters. (B) Plot of individual-predicted vs. observed sum of tumour diameters. (C) Plot of the conditional weighted residual error (CWRES) vs. time. (D) Plot of the conditional weighted residual error (CWRES) vs. population predicted sum of tumour diameters. The solid line in panel A and B is the line of identity (observed=predicted)

Figure 5

Simulation of the time course of drug effect in 5000 patients taking BYL719 (A) 400 mg once daily vs. no treatment, or (B) 200 mg twice daily vs. no treatment. All patients were assumed to have a baseline sum of tumour diameters of 10 cm. Simulation of the BYL719 plasma concentration time profile in 5000 patients taking BYL719 (C) 400 mg once daily or (D) 200 mg twice daily. The dashed line is the 50^th percentile (median). The lower and upper solid lines represent the 5^th and 95^th percentile of simulated data. Horizontal reference lines indicate the estimated IC₅₀ (101 ng ml⁻¹) and IC₈₀ (404 ng ml⁻¹) of BYL719 on tumour growth