Trial lecture title: Non-genetic factors that cause variation in drug pharmacokinetics and pharmacodynamics.
Ordinary opponents:
- First opponent: Associate Professor Tore Bjerregaard Stage, University of Southern Denmark
- Second opponent: Senior Engineer Helle Høyer, Telemark Hospital Trust, Norway
- Chair of the evaluation committee: Associate Professor Lene Berge Holm, OsloMet
Leader of the public defence is Professor Ellen Karine Grov, OsloMet.
The main supervisor is Associate Professor Marianne Kristiansen Kringen, OsloMet. The co-supervisor is Professor Espen Molden, Diakonhjemmet Hospital.
Thesis abstract
Drug therapy is a commonly used option in treatment of depression, but therapeutic failure (insufficient or adverse effects) is frequent and occur in about one third of the patients.
Especially, in patients with ultrarapid drug metabolism it may be challenging to achieve sufficient effect due to under-exposure at standard recommended dosing. To date, ultrarapid metabolism is explained by genetics to a limited extent.
Although gene promoter variation in the CYP2C19 gene (CYP2C19*17) is a known mechanism for increased CYP2C19 activity, this variant cannot explain the vast majority of patients in need of increased dose of antidepressants for optimal drug exposure.
Thus, increased knowledge of gene variants causing ultrarapid CYP2C19 phenotype would be helpful in the guidance to personalized treatment of depression.
Aim
The aim of the present thesis was to identify novel CYP2C19 variants associated with increased CYP2C19 activity towards the antidepressants escitalopram and sertraline, as these are drugs subjected to extensive variability of the CYP2C19 gene.
Methods
To identify novel CYP2C19 variants, a targeted NGS analysis was performed in the CYP2C18/CYP2C19 locus in patients previously genotyped as CYP2C19*1/*1 and having an ultrarapid metabolism of escitalopram.
Results
A novel CYP2C-haplotype comprising the variants rs2860840T and rs11188059G (CYP2C:TG) was identified among patients exhibiting an unexplained ultrarapid metabolism. Homozygous carriers of CYP2C:TG had significantly reduced serum concentration of 24 percent (p = 0.008) and 20 percent (p = 0.022) for escitalopram and sertraline, respectively, compared to normal metabolisers not carrying this haplotype.
The effect of CYP2C:TG was in the same magnitude as for CYP2C19*17. In addition, a substantial and significant effect of CYP2B6 genotypes on serum concentration of sertraline was found (p < 0.02).
Conclusion
The present thesis identified a novel CYP2C-variant haplotype (CYP2C:TG) encoding ultrarapid CYP2C19 activity. Patients who are homozygous carriers of CYP2C:TG or CYP2C:TG/CYP2C19*17 are at increased risk of subtherapeutic drug exposure and treatment failure at standard recommended dosing.
Further studies should investigate the mechanism of which CYP2C:TG cause increased rate of metabolism and the impact of this novel haplotype on other important drugs metabolised by CYP2C19.
The identification of this biomarker for rapid drug metabolism may improve treatment efficacy in patients with depression and could contribute to lowering the toxicity and adverse effects of antidepressants and other drug metabolised by CYP2C19.
