Omeprazole and esomeprazole narrowed the CYP2C19 genotype effect on escitalopram more than pantoprazole

Design

Retrospective cohort from a therapeutic drug monitoring and pharmacogenetics laboratory, with mass spectra reprocessed to detect co-medication

Population

2,818 CYP2C19-genotyped patients on escitalopram in Oslo, Norway; 445 with a proton pump inhibitor

Primary outcome

N-desmethylescitalopram-to-escitalopram metabolic ratio, ultrarapid vs poor metabolisers

Effect

4.5-fold higher without proton pump inhibitor; 2.8-fold with pantoprazole (P < 0.001); 1.8-fold with esomeprazole or omeprazole (P = 0.2)

This study used a combined therapeutic drug monitoring and pharmacogenetics laboratory in Oslo. High-resolution mass spectra from drug monitoring samples were reprocessed to identify possible co-medication with a proton pump inhibitor, in 2,818 CYP2C19-genotyped patients. Of these, 445 (15.8%) had a proton pump inhibitor detected. The phenotype split was 39.3% normal, 29.3% intermediate, 2.6% poor, 24.6% rapid and 4.2% ultrarapid metabolisers.

The ratio of the metabolite N-desmethylescitalopram to escitalopram, a marker of CYP2C19 activity, was 4.5-fold higher in ultrarapid than poor metabolisers without a proton pump inhibitor, 2.8-fold with pantoprazole (P < 0.001) and 1.8-fold with esomeprazole or omeprazole (P = 0.2). In other words, these drugs reduced the difference between genotype groups, more strongly for esomeprazole and omeprazole.

The design is observational and the drugs were identified from spectra, so the study cannot tell whether doses should change, and it measured no clinical outcomes. For a prescriber, the point is practical: a patient on escitalopram and a proton pump inhibitor may not behave as their genotype predicts, and if a switch is needed, pantoprazole interferes least of the ones studied.

• The metabolic ratio gap between ultrarapid and poor metabolisers was 4.5-fold without a proton pump inhibitor.
• It was 2.8-fold with pantoprazole and 1.8-fold with esomeprazole or omeprazole.
• About 1 in 6 patients (15.8%) in this drug-monitoring service had a proton pump inhibitor detected.
• Ask about omeprazole or esomeprazole when escitalopram response or levels do not fit the genotype.
• No outcome data were collected, so do not change doses on this study alone.

Why it matters

It shows that a very common co-prescription can make a genotype report misleading for a very common antidepressant.

Don't overread it

This is a laboratory-based observational analysis of drug ratios, not a clinical outcome study, and the proton pump inhibitor exposure was inferred from spectra.

The statistics, in plain English

A fold-difference of 4.5 versus 1.8 in the metabolic ratio between genotype groups means the proton pump inhibitor erased much of the genotype effect. The omeprazole and esomeprazole group was small, so its P value of 0.2 does not show there was no gap, only that the study could not tell.

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