David J. Lunn & Leon Aarons
Department of Epidemiology and Public Health, Imperial College School of Medicine at St. Mary’s, Norfolk Place, London W2 1PG, Department of Pharmacy, University of Manchester, Manchester M13 9PL.
Saquinavir is an HIV proteinase inhibitor currently being developed as a treatment for HIV infection. The drug has potent (Ki ~ 0.1 nM) antiviral activity and acts by inhibiting the processing of gag and gag-pol polyproteins, thus blocking the maturation of replicated viral particles. By assuming standard two-compartment disposition kinetics in combination with a variety of absorption processes we have identified two structural models that perform well with respect to describing the pharmacokinetic behaviour of saquinavir when administered to healthy human volunteers from various phase I studies. These structural models have been implemented for population analysis of these phase I data via the Bayesian Markov chain Monte Carlo approach. These analyses revealed that saquinavir exhibits complex, highly variable, non-linear behaviour, but can be modelled adequately using a two-compartment zero-order absorption model.
To attempt to explain some of the extensive interindividual variability, the two-compartment zero-order absorption model was also applied to three sets of phase II saquinavir data. In total, eleven covariates were investigated. In cases where statistically significant effects were identified, the clinical significance of these effects was assessed by evaluating predictive distributions for various sub-populations. The results of these analyses will be presented and discussed.
Reference: PAGE 6 (1997) Abstr 595 [www.page-meeting.org/?abstract=595]
Poster: oral presentation