The role of cytochrome P450 polymorphisms in the pharmacokinetics of oral esketamine

Clinical Snapshot

Key Findings

• P Value: p = 0.032 (Mann-Whitney U test)

• Effect Size: 2.4-fold higher median plasma levels in CYP2B6 516 G>T carriers (5.1 vs 2.1 µg/L)

• Primary Outcome: Esketamine plasma concentrations at 4 hours post-dose

• Nnt Or Sensitivity: Not applicable - pharmacokinetic study without clinical outcomes

• Confidence Interval: Not reported

Clinical Application

Limited by very small sample size and lack of clinical outcome data Esketamine nasal spray available on PBS for treatment-resistant depression; oral formulation not yet approved by TGA. Pharmacogenetic testing not routinely recommended in RACGP guidelines for esketamine Patients with treatment-resistant depression considering oral esketamine therapy

Abstract

Oral esketamine displays therapeutic potential for treatment-resistant depression. However, treatment is complicated by a low and variable bioavailability. Genetic polymorphisms in the cytochrome P450 (CYP) enzymes responsible for esketamine's metabolism may influence bioavailability. In a subsample of patients included in a placebo-controlled trial investigating repeated, low dose oral esketamine (N = 18), blood samples were collected four hours after dosing. CYP2B6 516 G > T, CYP3A4*22, and CYP3A5*3 genotyping was performed, and the plasma levels of esketamine and its metabolites were measured. CYP2B6 516 G > T carriers (Mdn = 5.1 µg/L) demonstrated higher esketamine plasma levels compared to non-carriers (Mdn = 2.1 µg/L) (U = 45.00, p = 0.032). No significant associations were observed for CYP3A4*22 carriership (n = 2) or CYP3A5*3 heterozygosity (n = 2), nor for esketamine's metabolites. In summary, CYP2B6 516 G > T is associated with higher esketamine plasma concentrations. Further research with more participants is warranted to draw conclusions about CYP3A4*22 and CYP3A5*3. Clinical trial registration: NTR6161 (Dutch Trial Register).

References

1. 1.Coerts, D. T., Smith-Apeldoorn, S. Y., Oude Nijhuis, J. C., van Schaik, R. H. N., Tamminga, W. J., Touw, D. J., Veraart, J. K. E., Schoevers, R. A., & van Dalfsen, J. H. (2026). The role of cytochrome P450 polymorphisms in the pharmacokinetics of oral esketamine. The Pharmacogenomics Journal. https://doi.org/10.1007/s40262-020-00953-4