Optimal Designs for Non-Compartmental Analysis of Pharmacokinetic Studies

Abstract

In traditional toxicology trials, pharmacokinetics (PK) is investigated in the satellite group of animals, and the pharmacodynamics (PD) is investigated in the study group of animals. The new blood sampling method of microsampling opens up the opportunity to investigate both PK and PD in the same animals. To avoid excessive burden on the animals from the required blood sampling, sparse sampling schemes are typically used. Motivated by this application, this article introduces a procedure to choose an optimal sparse sampling scheme and sampling time points using non-compartmental methods but which can be applied to further settings beyond this. We discuss how robust designs can be obtained and we apply and evaluate the approach to a range of scenarios to give an example of how it may be implemented. The results are compared to optimal designs for model based PK. Supplementary materials for this article are available online.

Methods for Non-Compartmental Pharmacokinetic Analysis With Observations Below the Limit of Quantification

“…In batch sampling, the subjects are divided into batches with each batch of subjects all sampled at the same time points with no other subjects sampled at any of these time points (hence the time points for each batch form a partition of the set of all time points). Alternative sampling methods such as serial sampling, where restrictions on blood volume limit sample to one per subject and complete sampling where all subjects are sampled at all timepoints (allowed by innovative blood sampling methods such as microsampling (Chapman et al 2014;Barnett et al 2018) are often used. These are special cases of batch sampling, and hence this generalized form of the variance approximation can also be used in these cases.…”

Assessing the inter-patient variability in the area under the concentration curve

“…Jawień (2014) proposed a method for the construction of a linear estimator of the AUC in a finite interval that is optimal in the minimax sense. Barnett et al (2018) proposed a method of producing optimal designs for non-compartmental analysis of pharmacokinetic study. Bailer (1988) described an way to find the AUC from destructive sampling by using the trapezoidal rule.…”