Stephen Duffull1,2, France Mentré3, Leon Aarons1
1) School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Rd, Manchester, M13 9PL, UK. 2) School of Pharmacy, University of Queensland, Brisbane, QLD 4069, Australia. 3) INSERM U 436, CHU Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75013 Paris, France
Background: Methods for optimal design of population pharmacokinetic experiments using the population Fisher information matrix (PF) have been developed recently. There are no studies that have addressed the optimal design of population pharmacodynamic experiments by assessment of the PF. Optimisation of a population pharmacodynamic is shown here using ivabradine as an example. Ivabradine is a novel bradycardic agent that has been developed for the prevention of myocardial ischaemia.
Aim: To design a parsimonious population pharmacodynamic experiment for ivabradine that has the same or greater efficiency than that provided by two phase I studies that were used in the original model construction process. The two phase I studies were concatenated for the purposes of comparison.
Methods: The PF was estimated using methods described previously. Options for optimisation were: 1) determination of the optimal sampling times for each group (“group” represents a group of subjects that have identical design characteristics, 2) determination of the optimal doses for each group and 3) determination of the optimal group structure.
Results: 1) Optimising the sampling times, while retaining only 4 unique times per group (giving 312 samples in total), provided a more parsimonious experiment than the original study(s), which involved on average 10 samples per subject (768 samples in total). Splitting sampling times between the first dose and a steady-state dose gave the most informative design. 2). The optimal dose was the same in all groups and was the upper bound of the dose range. 3) The optimal population design consisted of only 1 group with 4 unique sampling times that were the same for all subjects.
Discussion: A population pharmacodynamic trial design is presented that is more parsimonious than the baseline design and would be appropriate for inclusion in a later phase clinical study.
Supported by grant BIOMED PL 962640 from E.C
Reference: PAGE 9 (2000) Abstr 81 [www.page-meeting.org/?abstract=81]
Poster: oral presentation