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.
Kathman
S J
SJ
GlaxoSmithKline, Research Triangle Park, North Carolina, USA. steven.kathman@gsk.com
Williams
D H
DH
Hodge
J P
JP
Dar
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001499:Bayes Theorem; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced*; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D011799:Quinazolines; C508757:ispinesib