2004
   Uppsala, Sweden

Bayesian Population Pharmacokinetic Analysis of Sirolimus

C. Dansirikul(1), L.E. Friberg(1), S.B. Duffull(1), R.G. Morris(2), S.E. Tett(1)

(1)School of Pharmacy, University of Queensland, Brisbane, Australia; (2) Dept. of Clinical Pharmacology, The Queen Elizabeth Hospital, Adelaide, Australia

Objective: It is usual that data collected from routine clinical care is sparse and unable to support the more complex pharmacokinetic (PK) models that may have been reported in previous rich data studies. Informative priors may be a pre-requisite for model development. The aim of this study was to estimate the population PK parameters of sirolimus using a fully Bayesian approach with informative priors.

Methods: Informative priors including prior mean and precision of the prior mean were elicited from previous published studies using a meta-analytic technique. Precision of between-subject variability was determined by simulations from a Wishart distribution using MATLAB (version 6.5). Concentration-time data of sirolimus retrospectively collected from kidney transplant patients were analysed using WinBUGS (version 1.3). The candidate models were either one- or two-compartment with first order absorption and first order elimination. Model discrimination was based on computation of the posterior odds supporting the model.

Results: A total of 315 concentration-time points were obtained from 25 patients. Most data were clustered at trough concentrations with range of 1.6 to 77 hours post-dose. Using informative priors, either a one- or two-compartment model could be used to describe the data. When a one-compartment model was applied, information was gained from the data for the value of apparent clearance (CL/F = 18.5 L/h), and apparent volume of distribution (V/F = 1406 L) but no information was gained about the absorption rate constant (k_a). When a two-compartment model was fitted to the data, the data were informative about CL/F, apparent inter-compartmental clearance, and apparent volume of distribution of the peripheral compartment (13.2 L/h, 20.8 L/h, and 579 L, respectively). The posterior distribution of the volume distribution of central compartment and k_a were the same as priors. The posterior odds for the two-compartment model was 8.1, indicating the data supported the two-compartment model.

Conclusion: The use of informative priors supported the choice of a more complex and informative model that would otherwise have not been supported by the sparse data.