Studies on intrinsic and extrinsic sources of variability in pharmacokinetics and pharmacodynamics

Sammanfattning: Variability in pharmacokinetic and pharmacodynamic parameters between individuals can be due to intrinsic and extrinsic factors. In this thesis three different areas regarding sources of variability have been investigated. 1. Formulation properties as an extrinsic source of variability. Lipophilic substances often have poor oral bioavailability and high inter- and intraindividual variability. High fat meals can increase the bioavailability. Two lipophilic substances, astaxanthin and cyclosporine, were incorporated in different lipid based formulations, given orally to healthy volunteers, and shown to alter the bioavailability when compared to reference substances. The combination of different lipid excipients, their ratios and the degree of drug incorporation were factors shown to affect the drug bioavailability. The use of a rational formulation approach in the study with cyclosporine gave successful information in a limited number of trials. 2. Intrinsic and extrinsic sources of variability in the pharmacokinetics and pharmacodynamic of desmopressin. To evaluate factors that can cause variability both the pharmacokinetics and pharmacodynamics have to be investigated. Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. We studied in humans if different levels of water hydration had any influence on especially the pharmacokinetics, and found no statistical evidence for that. An indirect response model was described and verified for the concentration-effect relationship. Further, we investigated sex differences and the impact of concomitant medication with piroxicam , and we found a difference in the pharmacodynamics of desmopressin, but not in the pharmacokinetics. 3. Genetic polymorphism as an intrinsic source of variability in drug metabolism and drug transport. We investigated, in a Swedish cohort (248 individuals) and in a human diversity panel (HDP) (DNA from 14 ethnicities), the prevalence of different polymorphisms and haplotypes in the UGT1A- and MDR1-genes, both being associated with variations in pharmacokinetics. Also, to estimate UGT1A genotype-dependent glucuronidation efficiency, we used the endogenous substrate bilirubin as an indicator. We found that several of the genetic variants investigated in the UGT1A-gene and also the SNP (exon 26, C3435T) in the MDR1 gene are common in the cohort. The HDP indicated differences in prevalence of the allelic variants due to ethnicity. Three major haplotypes of the UGT1A-gene constitute 84% of the allelic variants. Tools for optimisation, prediction and individualisation of drug treatment are important for attaining the aim of explaining and reducing variability in drug response.