Cytochrome P450 2D6 genotypephenotype analyses for improved personalized medicine

Trine Frederiksen

Research output: ThesisPh.D. thesis

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Abstract

The cytochrome P450 (CYP) 2D6 enzyme is the predominant pathway for the elimination or bioactivation of numerous drugs. Due to genetic polymorphism of the CYP2D6 gene, individuals display varying degrees of CYP2D6 enzyme activity. This causes variability in drug exposure which in turn may result in differences in drug efficacy and tolerability. To guide personalized dosing of CYP2D6 substrates, it is essential to have a good understanding of the impact of CYP2D6 polymorphism on enzyme activity. The main objective of this PhD project was to quantify the CYP2D6 activity associated with various CYP2D6 genotypes and alleles by studying the pharmacokinetics (PK) of three different CYP2D6 substrates and their metabolites.

This thesis presents three population pharmacokinetic (popPK) studies characterizing the joint parent-metabolite PK of vortioxetine, tedatioxetine and brexpiprazole, respectively. Based on estimates from the final popPK models, the CYP2D6-mediated metabolism was quantified for more than 2,000 individuals carrying a wide range of CYP2D6 genotypes.

The analyses showed that decreased function alleles (e.g. CYP2D6*9, *10, *17 and *41) were generally associated with a more than 50% reduction of CYP2D6 enzyme activity relative to the wild-type (CYP2D6*1). Particularly, the CYP2D6*17 and *41 alleles showed lower than expected enzyme activity across the substrates, while CYP2D6*10 exhibited ~30% enzyme activity relative to CYP2D6*1 for all three substrates. It is worth highlighting that the normal function allele, CYP2D6*2, exhibited a substantially decreased enzyme activity in the biotransformation of brexpiprazole to DM-3412 suggesting substrate-specific activity of this allele. Collectively, the results indicate that CYP2D6 genotype-phenotype translation schemes could benefit from further refinement particularly with regards to decreased function alleles and substrate-specific behaviour.

Data from a therapeutic drug monitoring (TDM) unit was used to assess the performance of the popPK model developed for vortioxetine in a real-life clinical setting. Overall, the validation study showed a good ability of the popPK model to predict vortioxetine serum concentrations measured as part of routine clinical practice. The model had a slight tendency to overpredict concentrations, which may be partly due to the naturalistic nature of the TDM data. Longitudinal reviews of TDM profiles showed that CYP2D6 poor metabolisers (PMs) had an increased frequency of switching to an alternative antidepressant compared to normal metabolisers. This was paralleled by significantly higher exposures among the PMs, and therefore the higher rate of treatment switch might be explained by an increased risk of adverse events caused by supratherapeutic drug concentrations.

While this thesis contributes to the evidence of CYP2D6 genotype-phenotype relationships, several aspects remain to be addressed. Future studies should aim to evaluate poorly characterized CYP2D6 alleles and further investigations of the impact of factors such as pathology, ethnicity, transcription factors and microRNA could contribute to our understanding of CYP2D6. Lastly, to facilitate successful implementation of pharmacogenetics in the clinic, solid evidence of cost-effectiveness and adequate technical infrastructure remains to be established.
Translated title of the contributionCytokrom P450 2D6 genotype-fænotype analyser til forbedret personlig medicin
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Brøsen, Kim, Principal supervisor
  • Stage, Tore B., Co-supervisor
  • Areberg, Johan, Co-supervisor, External person
  • Schmidt, Ellen, Co-supervisor, External person
Publisher
DOIs
Publication statusPublished - 31. May 2022

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