Ivelina Gueorguieva, Leon Aarons, Karin M. Jorga and Malcolm Rowland
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom; Department of Research and Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland
Objective: To develop a methodology for individual and population multivariate response design for pharmacokinetic models. To suggest optimal sampling times for a restrospective iv bolus study for the disposition kinetics of tolcapone and its two metabolites in healthy volunteers.
Methods: We aim to design a study for efficient estimation of tolcapone and its metabolites, by employing a D-optimal design criterion. This criterion minimises the volume of the joint confidence region by maximising the determinant of the Fisher information matrix (FIM) (inverse of variance-covariance matrix). It was further assumed that measurements made at distinct times are independent, but measurements made of each drug tissue concentrations are correlated with a constant variance-covariance matrix. Following population data analysis in NONMEM, models for the univariate responses, e.g. considering only tolcapone disposition, and for the multiresponse situation, i.e. simultaneous analysis of tolcapone and its metabolites, were identified. Subsequently optimal sampling times were suggested for both individual and population designs. The effects of design variables, such as response covariance matrix, number of sampling times and structure of residual model were investigated. To determine the D-optimal design the determinant of the FIM has to be maximised over the whole design space. Unfortunately the surface of this determinant was very convoluted which places additional requirements on any optimiser. A number of optimisation methods (downhill simplex, simulated annealing, adaptive random search, exchange) were used.
Results: The exchange algorithm and a hybrid scheme consisting of simulated annealing followed by downhill simplex performed the most consistently well. D-optimal sampling times for individual and population designs were obtained.
Conclusions: A methodology for population multivariate response design for PK experiments was suggested. This was illustrated by a retrospective study of the disposition of tolcapone and its metabolites in healthy volunteers.
References:
Draper and Hunter (1966) Biometrika 53: 525-533.
Reference: PAGE 14 (2005) Abstr 746 [www.page-meeting.org/?abstract=746]
Poster: poster