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Clin Pharmacol Ther. 2007 Jan;81(1):88-94.

A Bayesian population PK-PD model of ispinesib-induced myelosuppression.

Author information

1
GlaxoSmithKline, Research Triangle Park, North Carolina, USA. steven.kathman@gsk.com

Abstract

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.

PMID:
17186004
DOI:
10.1038/sj.clpt.6100021
[Indexed for MEDLINE]

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