Proton pump inhibitors blunt the CYP2C19 genotype signal for escitalopram, with omeprazole and esomeprazole the strongest

The edition in brief

In 2,818 CYP2C19-genotyped patients from a Norwegian therapeutic drug monitoring service, 445 (15.8%) had mass-spectrometry evidence of a proton pump inhibitor. The escitalopram metabolic ratio was 4.5-fold higher in ultrarapid than poor metabolisers without a proton pump inhibitor, 2.8-fold with pantoprazole and 1.8-fold with esomeprazole or omeprazole, so these drugs narrowed the gap between genotype groups, more so for omeprazole and esomeprazole. A pharmacovigilance paper re-examined the fezolinetant neoplasm signal: non-benign neoplasms rose across placebo, 30 mg and 45 mg (0.2, 0.7, 1.2 per 100 subject-years; relative risk at the licensed dose 6.6, 95% CI 0.9 to 51.3), not statistically significant, and the authors argue the regulatory reasoning for dismissing it was weak and call for surveillance. A single case report of a man in his sixties starting lenacapavir with long-standing primidone found concentrations stayed above the target threshold and the viral load stayed undetectable, although the combination is not recommended in labelling. A meta-analysis of eight trials found response and remission higher with one commercial pharmacogenomic panel in three trials (RR 1.30 and 1.53) but heterogeneous and imprecise effects across other panels.