Analysis of Combined Effect of CYP2C19 Genetic Polymorphism and Proton Pump Inhibitors Coadministration on Trough Concentration of Voriconazole

Purpose: To analyze the combined effect of CYP2C19 genetic polymorphism and PPIs coadministration on voriconazole trough concentration (VCZ-C-trough) in Chinese patients with hematological disorders. Patients and Methods: A prospective observational study involved 250 plasma sam -ples from 114 adult patients receiving voriconazole with or without PPIs were ana-lyzed. Demographics and clinical characteristics were obtained from patient's records. A validated LC-MS/MS was used to quantify the plasma VCZ-C-trough. Genotyping for CYP2C19*2 and CYP2C19*3 variant alleles was performed by PCR-RFLP followed by DNA sequencing. The combined total score (from 2 to 5) was calculated for each patient. The higher the score, the lesser the metabolism of the patient. Findings: Fifty percent of patients administered with voriconazole were coadministered with PPIs, predominantly omeprazole or esomeprazole. Patients exhibiting CYP2C19 poor metabolizer phenotype showed a significantly higher median VCZ-C-trough, (4.31 mu g/mL [IQR, 1.64 mu g/mL-7.36 mu g/mL]) than patients with normal metabolizer (1.38 mu g/mL, [IQR, 0.79 mu g/mL-2.14 mu g/mL], p < 0.0001). Similarly, patients co-administration with PPIs had higher median VCZ-C-trough (2.86 mu g/mL [IQR 1.33 mu g/mL-4.66 mu g/mL]), than PPIs non-users (1.71 mu g/mL, [IQR, 0.86 mu g/mL-3.48 mu g/mL], p = 0.001). However, we noted that the median VCZ-C-trough for each factor was ranging within the normal recommended therapeutic range in the Chinese population (0.5 mu g/mL-5 mu g/mL). But when the two factors were combined, the median VCZ-C-trough was steadily increasing as the metabolic capacity (reflected by combined total score) was increasing. Importantly, the median VCZ-C-trough in PM/PPIs user (total score 5) was significantly elevated to supra-therapeutic levels compared to NM/PPI non-user group (total score 2) (5.83 mu g/mL [IQR, 2.19 mu g/mL-9.51 mu g/mL] versus 1.13 mu g/mL [IQR, 0.67 mu g/mL-1.82 mu g/mL]), respectively, P < 0.0001. Furthermore, we observed that the elevation of median VCZ-C-trough to supra-therapeutic levels was largely contributed by omeprazole or esome-prazole compared to lansoprazole or pantoprazole. Conclusion: Coadministration with PPIs significantly increased voriconazole trough con-centrations and there was an additive effect in CYP2C19 PMs, who were most likely to have supra-therapeutic levels.