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<p>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 (<i>N</i> = 18), blood samples were collected four hours after dosing. <i>CYP2B6</i> 516 G &gt; T<i>, CYP3A4*22</i>, and <i>CYP3A5*3</i> genotyping was performed, and the plasma levels of esketamine and its metabolites were measured. <i>CYP2B6</i> 516 G &gt; T carriers (<i>Mdn</i> = 5.1 µg/L) demonstrated higher esketamine plasma levels compared to non-carriers (<i>Mdn</i> = 2.1 µg/L) (<i>U</i> = 45.00, <i>p</i> = 0.032). No significant associations were observed for <i>CYP3A4*22</i> carriership (<i>n</i> = 2) or <i>CYP3A5*3</i> heterozygosity (<i>n</i> = 2), nor for esketamine’s metabolites. In summary, <i>CYP2B6</i> 516 G &gt; T is associated with higher esketamine plasma concentrations. Further research with more participants is warranted to draw conclusions about <i>CYP3A4*22</i> and <i>CYP3A5*3</i>. Clinical trial registration: NTR6161 (Dutch Trial Register)</p>

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

  • 期刊论文

  • 发表日期：

    2026年4月24日

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  • Daniël T. Coerts,
  • Sanne Y. Smith-Apeldoorn,
  • Jérôme C. Oude Nijhuis,
  • Ron H. N. van Schaik,
  • Wim J. Tamminga,
  • Daan J. Touw,
  • Jolien K. E. Veraart,
  • Robert A. Schoevers,
  • Jens H. van Dalfsen

摘要

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)