Assessment of the influence of demographic and anthropometric indicators on the variability of pharmacokinetic parameters

Abstract

Relevance. Planning the design of bioequivalence clinical studies of generic highly variable drugs requires non-standard approaches – the use of replicative (repeated) or adaptive design. However, both approaches entail an increase in organizational, time, and financial costs. Therefore, it becomes relevant to search for ways to pre-select volunteers with a lower initial level of variability in pharmacokinetic parameters to reduce the number of subjects.Objective. The aim of this study was to determine the potential subjects in clinical trials with a low initial level of variability in pharmacokinetic parameters using methods for assessing initial gender – age and anthropometric and clinical laboratory parameters.Material and methods. Data from clinical studies of the bioequivalence of drugs (valganciclovir, carebastine and raltegravir) with different levels of variability conducted in the period 2020–2022 in Russia were used for analysis. To achieve this goal, a model for grouping pharmacokinetic parameters (PhK) with known demographic and clinical laboratory parameters was developed using discriminant analysis. Discrimination was performed between optimal pharmacokinetics (OPhK) and variable pharmacokinetics (VPhK). Mathematical and statistical analyses of the results were performed using Microsoft Excel 2013 and Statistica 10.0.Results. During the study, the variability of the maximum concentration of the drug in plasma (Cmax), including its logarithmic values, was used as a basis. The levels of intra-individual variability (CVintra), which is the main characteristic of drug variability, in the OPhK group were several times lower than those in the VPhK group for all studied drugs, but for the highly variable drug raltegravir, they differed by almost 10 times.Conclusion. Therefore, the obtained results indicated that using traditional gender – age and anthropometric indicators alone is impossible to separate the OPhK and VPhK groups for the analyzed drugs with high PhK variability.

Keywords

• highly variable drug
• pharmacokinetic parameters
• age
• anthropometric characteristics
• healthy volunteers
• bioequivalence
• clinical studies