Two common transporter gene variants did not change oral esketamine blood levels (n=18)

The question

Do common variations in two genes that control ‘pump’ proteins in the gut and elsewhere (ABC transporters) affect how much esketamine ends up in the blood after it is swallowed?

What they did

Researchers used blood samples from 18 people taking part in a placebo-controlled trial of repeated low-dose oral esketamine for treatment-resistant depression. Each person was genotyped for two common gene variants, ABCB1 3435C>T and ABCG2 421C>A. Plasma levels of esketamine and its breakdown products were measured 4 hours after a dose and compared across genotype groups.

What they found

For ABCB1 3435C>T, median esketamine concentrations were 3.8 µg/L for C/C, 2.7 µg/L for C/T and 1.0 µg/L for T/T, a difference that was not statistically significant (p = 0.182). For ABCG2 421C>A, medians were 1.5 µg/L for C/A and 2.4 µg/L for C/C, also not significantly different (p = 0.471). Levels of esketamine’s metabolites were likewise not linked to genotype. The authors describe the findings as preliminary.

The fine print

Only 18 people were included, and some genotype groups contained very few individuals, so a real effect could easily have been missed. Only a single blood measurement at 4 hours after dosing was used, which is a limited picture of how the drug moves through the body. The study measured drug levels, not depression outcomes. This summary is based on the abstract alone.

What it means

In this small sample, two common transporter gene variants did not clearly explain why blood levels of oral esketamine vary between people; much larger studies are needed before genetics could guide individual dosing.

Evidence grade: Very low. A small genetic sub-study of 18 people drawn from an existing trial, with few carriers of each gene variant, so it cannot reliably detect modest effects.

This summary is based on the study’s published abstract.