Doctoral thesis

Assessing the intrinsic and extrinsic factors of pharmacokinetic variability for precision medicine:A focus on CYP2C19 and the influence of genetic polymorphisms on drug interactions

ContributorsAbouir, Kenza
Number of pages147
Imprimatur date2024
Defense date2024

Precision medicine, also known as personalized medicine, aims to tailor treatments and care according to the specific characteristics of each individual, opposed to the one-size-fits-all approach, recognizing the uniqueness of each patient.

It takes into account intra- and inter-individual variability resulting from intrinsic factors such as genetic polymorphism or existing pathologies, as well as environmental factors.

In general, individual response to pharmacological treatment is influenced by drug disposition in the body (pharmacokinetics, PK) and effects on the therapeutic target (pharmacodynamics, PD). Drug pharmacokinetics depend on absorption into the systemic circulation, tissue distribution, metabolism, and elimination. Pharmacokinetic variability mainly manifests in metabolism, particularly hepatic cytochrome P450 enzymes (CYP450), which metabolize about 75% of drugs on the market and exhibit significant genetic polymorphism. This genetic polymorphism, combined with other environmental or physiological factors, can greatly impact therapeutic efficacy and safety.

To date, the impact of genetic polymorphism and drug interactions on the expression and activity of CYP450s concerning the pharmacokinetics of CYP450 substrate drugs have been extensively studied separately.

The objective of this thesis is to study the impact of genetic polymorphism on drug interactions involving CYP2C19. The thesis is divided into six chapters, briefly outlined as follows:

  • Introduction to the concept of drug response variability in precision medicine, emphasizing the importance of CYP450s and exploring various intrinsic and extrinsic factors influencing pharmacokinetic parameters, particularly the activity and/or expression of CYP450s.
  • Development of a sensitive and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying enantiomers of omeprazole and its hydroxylated metabolite in human plasma.
  • Application of the developed method to evaluate the potential use of omeprazole enantiomers for CYP2C19 phenotyping.
  • Prospective study evaluating drug interaction exposure in three groups of volunteers based on their CYP2C19 genotype, highlighting the complex interaction of genetic polymorphism and medication involving CYP2C19.
  • Prospective observational study assessing the impact of weight and sex on dexamethasone exposure, particularly in the context of the COVID-19 pandemic.
  • General discussion of thesis results, conclusions, and future perspectives.
  • eng
    • CYP450
    • Pharmacogenetics
    • Genetic polymorphism
    • Precision medicine
    Citation (ISO format)
    ABOUIR, Kenza. Assessing the intrinsic and extrinsic factors of pharmacokinetic variability for precision medicine:A focus on CYP2C19 and the influence of genetic polymorphisms on drug interactions. 2024. doi: 10.13097/archive-ouverte/unige:175947
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    Creation03/13/2024 3:27:44 PM
    First validation03/26/2024 2:21:40 PM
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