Robust optimal design for the estimation of hyperparameters in population pharmacokinetics

The expectation of the determinant of the inverse of the population Fisher information matrix is proposed as a criterion to evaluate and optimize desi gns for the estimation of population pharmacokinetic (PK) parameters. Given a PK model, a measurement error model, a parametric distribution of the pa rameters and a prior distribution representing the belief about the hyperpa rameters to be estimated the EID criterion is minimized in order to find th e optimal population design. In this approach, a group is defined as a numb er of subjects to whom the same sampling schedule (ie., the number of sampl es and their timing) is applied. The constraints, which are defined a prior i, are the number of groups, the size of each group and the number of sampl es per subject in each group. The goal of the optimization is to determine the optimal sampling times in each group. This criterion is applied to a on e-compartment open model with first-order absorption. The error model is ei ther homoscedastic or heteroscedastic with constant coefficient of variatio n. Individual parameters are assumed to arise from a lognormal distribution with mean rector M and covariance matrix C. Uncertainties about the hi and C are accounted for by a prior distribution which is normal for M and Wish art for C. Sampling times are optimized by using a stochastic gradient algo rithm. influence of the number of different sampling schemes, the number of subjects per sampling schedule, the number of samples per subject in each sampling scheme, the uncertainties on hi and C and the assumption about the error model and the dose have been investigated.