Abstract A195: A population pharmacokinetic (PPK) model of bosutinib (BOS).

Abstract

Abstract BOS is an orally active, dual Src/Abl kinase inhibitor. BOS has demonstrated efficacy and acceptable safety in patients (pts) with Philadelphia chromosome-positive (Ph+) leukemia. A PPK model was developed for BOS using pooled clinical data from a phase 1 trial of pts with advanced solid tumors given BOS 50 to 600 mg/d with food; a phase 1/2 trial of pts with tyrosine kinase inhibitor-resistant/intolerant Ph+ leukemia given BOS 400 to 600 mg/d with food; and a phase 3 trial of pts with newly diagnosed Ph+ chronic phase chronic myeloid leukemia given BOS 500 mg/d with food. 870 pts contributed to the PK analysis (typically 6–9 PK samples/pt). Pts were aged 18 to 91 y and weighed 35 to 221 kg. The final BOS PPK model was a 2-compartment model with first-order absorption and an absorption lag. PPK parameters were estimated with acceptable precision (see Table). The volume of the peripheral compartment was large with a slow turnover, and time to peak concentration was 5 to 6 h. The estimated alpha half-life was 19 h, with 68% and 32% of area under the curve (AUC) attributable to the alpha and beta half-lives, respectively. Residual unexplained variability was 30% at doses ≤100 mg and 32% at doses >100 mg. Dose-dependency in relative bioavailability (F) was seen, mostly at lower doses. PPK showed high inter-individual variability (IIV), consistent with high variability in BOS absorption. The lower F inferred for low doses could be accounted for by saturable active transport of bosutinib into the gut lumen, which shows more variability than absorption by passive diffusion. Baseline demographics and lab results could not account for the high IIV, and adjusting the BOS dose for body size was not beneficial. Model simulations showed that median AUC and peak concentration (Cmax) at steady-state were 4,322 ng/mL•h and 215 ng/mL, respectively, for BOS 500 mg/d. Within individuals, differences between peak and trough concentrations were relatively small, with a population fluctuation ratio (Cmax/Cmin) of 152%. BOS approached steady-state after 4 days, but concentrations were predicted to rise slowly during maintenance, characteristic of a drug with a large peripheral distribution volume. The model-based accumulation index was 2.45, which is in agreement with the 2- to 3-fold increase inferred from noncompartmental analysis. In conclusion, the PPK model of BOS showed acceptable descriptive and predictive performance, suitable for deriving individual exposure metrics for subsequent pharmacodynamic analyzes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A195.