A Bayesian Population PK-PD Model of Ispinesib-induced Myelosuppression

The goal of the present analysis is to fit a Bayesian population pharmacokinetic pharmacodynomic (PK-PD) model to characterize the relationship between the concentration of ispinesib and changes in absolute neutrophil counts (ANC). Ispinesib, a kinesin spindle protein (KSP) inhibitor, blocks assembly of a functional mitotic spindle, leading to G2/M arrest. A first time in human, phase I open-label, non-randomized, dose-escalating study evaluated ispinesib at doses ranging from 1 to 21 mg/m(2). PK-PD data were collected from 45 patients with solid tumors. The pharmacokinetics of ispinesib were well characterized by a two-compartment model. A semimechanistic model was fit to the ANC. The PK and PD data were successfully modelled simultaneously. This is the first presentation of simultaneously fitting a PK-PD model to ANC using Bayesian methods. Bayesian methods allow for the use of prior information for some system-related parameters. The model may be used to examine different schedules, doses, and infusion times.