Clozapine and norclozapine pharmacokinetic interaction with pantoprazole

Abstract Aims Clozapine is the first‐line treatment for resistant schizophrenia. However, clozapine concentrations should be monitored, especially in the case of drug–drug interactions. The current work aimed to assess the clozapine interaction with pantoprazole. Methods This was a randomized open‐label crossover study involving 12 healthy volunteers. The participants received a single dose of clozapine 12.5 mg in the two phases of the study alone or following five daily doses of pantoprazole 40 mg to be started 4 days before the clozapine dose, separated by a minimum of 2‐week washout period. 144 samples were collected at 30 min, 1, 2, 3, 5 and 8 h following a single dose of clozapine 12.5 mg. The clozapine and norclozapine concentrations were determined using a validated HPLC‐UV protocol. Results The pantoprazole treatment group had 8.7% lower clozapine bioavailability and lower maximum concentration (C max ) and area under the curve (AUC (0‐8) ) by 8.9% (95% confidence intervals [95% CI], 6.7%–11.0%) and 9% (95% CI, 7.2–10.8%), respectively, as well as significantly lower norclozapine C max and AUC (0–8) by 8.2% (95% CI, 6.3%–10.2%) and 8.5% (95% CI, 7.3%–9.7%), respectively. However, no significant difference was found in the norclozapine AUC (0–8) to clozapine AUC (0–8) ratio between the two treatment groups. Conclusions The concurrent intake of pantoprazole decreased the clozapine and norclozapine exposure, which was explained by the pantoprazole's impact on gastric acidity and clozapine absorption rather than on metabolizing enzymes. The interaction was not clinically relevant at low doses; however, clinicians should consider concomitant acid‐reducing agents when interpreting clozapine therapeutic drug monitoring results.