Designing population pharmacokinetic studies: performance of mixed designs.

The interplay of the following factors: population design (PDN), the cost function in terms of maximum cost (Max. C) (i.e., maximum number of samples/sample size), sample size, and intersubject variability [restricted (30%) to moderate (60%)] on the estimation of pharmacokinetic parameters from population pharmacokinetic data sets obtained using mixed designs was investigated in a simulation study. A two compartment model with multiple bolus intravenous inputs was assumed, and the residual variability was set at 15%. The sample size (N) investigated ranged from 30 to 200 with the associated cost function varying accordingly with the five individual and sixteen population designs studied. Accurate and precise estimates of structural model parameters were obtained for N > or = 50 (Max. C > or = 150) irrespective of the intersubject variability (ITV) and PDN investigated. When ITV was 30%, all structural model parameters were well estimated irrespective of the PDN. Robust estimates of clearance and its variability were obtained for all N at all levels of ITV with Max. C > or = 90 (PDN > or = 4). Imprecise estimates of ITV in V1, V2, and Q were obtained at 60% ITV irrespective of N, PDN, or Max. C. Positive bias was associated with the estimation of variability in V1, V2, and Q with PDN < or = 4 (Max. C < or = 150). This was due in part to a greater proportion of subjects sampled only once. Correspondingly, residual variability was underestimated. It is of utmost importance to avoid this artifact by ensuring that at least a moderate subset of subjects contributing data to a population pharmacokinetic study contribute data more than once. Given a sample size and ITV, the cost function must be considered in designing a population pharmacokinetic study using mixed designs.