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A Bayesian Population PK–PD Model of Ispinesib‐induced Myelosuppression
Author(s) -
Kathman SJ,
Williams DH,
Hodge JP,
Dar M
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100021
Subject(s) - pharmacokinetics , bayesian probability , pharmacology , population , medicine , oncology , mathematics , statistics , environmental health
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. Clinical Pharmacology & Therapeutics (2007) 81 , 88–94. doi: 10.1038/sj.clpt.6100021