Advanced population pharmacokinetic modelling to quantify selected characteristics of drugs

Abstract

The ophthalmic lyophilisate formulation has been known for its safety, tolerability, and ability to achieve higher concentrations of a drug in the internal tissue of the eye compared with the conventional eye drop. Based on this prior information, population pharmacokinetic modelling was executed and quantified an improvement in the absorption phase. These outcomes will generate novel concept to improve ocular drug delivery straightforward with patient care improvement.<br /> Modelling clarithromycin auto-inhibition started from the previous knowledge that clarithromycin decreases its own clearance with repeated dosing. A significant quantitative description of the size of inhibition boosts the faith in it to something approaching clinical impacts in efficacy of the administered doses, drug interaction and/or dose adjustment. The final model provides parameters for dose adjustment depending on patient body weight and MICs required for susceptible pathogen eradication. Combining available information about the MIC of a pathogen with the model parameter estimates provided a useful means to develop ideas toward optimization of therapy.<br /> The dextromethorphan study aimed to provide a clear picture of the metabolic activity of individual CYP2D6 alleles frequently observed in a healthy Caucasian population. Evaluations were based on prior knowledge of highly variable metabolism of CYP2D6 substrates, that is heavily dependent on CYP2D6 genotype, and the problem that phenotypic prediction is still pawned by the variability of metabolic activity of different alleles. Once the impact of individual alleles is quantitatively and significantly estimated, confidence in this approach is improved. These observations call for further evaluation of ethnic, substrate and disease impact, but for now it can be stated that these information are “highly” clinical relevant and significant towards therapeutic optimization.<br /> The phenprocoumon study aimed to identify genetic and demographic covariates for doseexposure response in a Caucasian population. Applications of previous knowledge of the role of evaluated covariates, led to confidence in the differential impact of both CYP2C9 polymorphisms on the exposure profiles and the contribution of VKORC1 polymorphisms to the overall phenprocoumon response. In addition to these findings, the differential activity of CYP2C9 alleles provided understanding of the importance of individualised drug dosing (based on genetic and demographic information) to phenprocoumon PK-PD profiles. This is not only of clinical importance in order to avoid overanticoagulation or therapy failure, but it will also decrease therapy expenses.