Coerts, D.T. (2024) Exploring the associations between genetic polymorphisms and oral esketamine’s pharmacokinetics. thesis, Medicine.
Full text available on request.Abstract
Background Oral esketamine displays therapeutic potential for treatment-resistant depression (TRD), but doses must be titrated individually due to a low and variable bioavailability. The genetic polymorphisms CYP3A4*22, ABCB1 C3435T, and ABCG2 C421A are hypothesised to influence esketamine’s oral bioavailability. The aim of this study is to investigate the associations between the polymorphisms and the plasma levels of esketamine and its metabolites. Methods Our study cohort was a subsample of a randomised controlled trial investigating fixed low-dose generic oral esketamine in addition to established antidepressant medication in patients with TRD. Genotypes and plasma levels were determined in blood collected four hours after esketamine intake. Results The study cohort consisted of 29 patients. None of the polymorphisms was found to be significantly associated with the plasma levels of esketamine and its metabolites. Still, our results showed trends towards higher esketamine (3.6 μg/L versus 2.0 μg/L (p=0.106)) and noresketamine (NK; 122.9 μg/L versus 51.7 μg/L, p=0.062) levels among carriers of CYP3A4*22. The trend for NK became significant in a post hoc analysis without patients who deviated from protocol (p=0.041). Conclusions CYP3A4*22 may impair esketamine’s metabolism. In contrast, the relevance of ABCB1 C3435T and ABCG2 C421A seems limited. We recommend further research in CYP3A4*22 together with other potentially relevant polymorphisms to confirm and quantify their impact on esketamine’s pharmacokinetics.
| Item Type: | Thesis (UNSPECIFIED) |
|---|---|
| Supervisor name: | Smith-Apeldoorn, drs. S.Y. and Dalfsen, dr. J.H. van and Schoevers, prof. dr. R.A. |
| Faculty: | Medical Sciences |
| Date Deposited: | 27 Jan 2025 11:45 |
| Last Modified: | 27 Jan 2025 11:45 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/3794 |
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