Bayesian derivation of an oral cancer slope factor distribution for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

The tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is classified by the International Agency for Research on Cancer as a Group 1 carcinogen. Cancer risk assessment in humans exposed to TSNAs largely relies on potency values estimated from animal studies, but available cancer potency values for NNK derived from such studies are conflicting. In this analysis, oral cancer slope factors (CSFo) for NNK were derived according to U.S. Environmental Protection Agency guidelines. An animal study in which rats were exposed to NNK in drinking water was selected as the key study. The multistage-cancer model was fit to the tumor incidence data to determine a point of departure for low dose linear extrapolation, using a benchmark response of 10%. CSFo distributions were then computed using Bayesian methods and Monte Carlo simulation. The resultant CSFo point estimate (BMR/BMDL(10)) was 19.2 (mg/kg day)(-1) based on lung tumor data and 12.2 (mg/kg day)(-1) based on pancreatic tumors. The 95th percentiles of the CSFo distributions were 27.3 and 19.3 (mg/kg day)(-1) based on lung and pancreatic tumors, respectively. The approach using Bayesian methods better accounts for the uncertainty inherent in the values generated using input assumptions and provides for a more robust probabilistic dose-response assessment.

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.