Pharmacogenomics and Personalized Medicine (Nov 2021)
Analysis of Combined Effect of CYP2C19 Genetic Polymorphism and Proton Pump Inhibitors Coadministration on Trough Concentration of Voriconazole
Abstract
Magesa Mafuru,1,2 Sanlan Wu,2 Henry Mayala,2 Zaituni Msengwa,3 Amani Phillip,1 Charles Mgone1 1Department of Clinical Pharmacology & Therapeutics, Hubert Kairuki Memorial University, Dar es Salaam, Tanzania; 2Department of Pharmacy, Union Hospital of Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Biological and Preclinical Studies, Muhimbili University of Health and Allied Sciences, Dar es Salaam, TanzaniaCorrespondence: Magesa MafuruDepartment of Clinical Pharmacology & Therapeutics, Faculty of Medicine, Hubert Kairuki Memorial University, P.O.Box 65300, Dar es Salaam, TanzaniaTel +255743917172Email [email protected]; [email protected]: To analyze the combined effect of CYP2C19 genetic polymorphism and PPIs coadministration on voriconazole trough concentration (VCZ-Ctrough) in Chinese patients with hematological disorders.Patients and Methods: A prospective observational study involved 250 plasma samples from 114 adult patients receiving voriconazole with or without PPIs were analyzed. Demographics and clinical characteristics were obtained from patient’s records. A validated LC-MS/MS was used to quantify the plasma VCZ-Ctrough. 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-Ctrough, (4.31μg/mL [IQR, 1.64μg/mL– 7.36μg/mL]) than patients with normal metabolizer (1.38μg/mL, [IQR, 0.79μg/mL– 2.14μg/mL], p < 0.0001). Similarly, patients co-administration with PPIs had higher median VCZ-Ctrough (2.86μg/mL [IQR 1.33μg/mL– 4.66μg/mL]), than PPIs non-users (1.71μg/mL, [IQR, 0.86μg/mL– 3.48μg/mL], p = 0.001). However, we noted that the median VCZ-Ctrough for each factor was ranging within the normal recommended therapeutic range in the Chinese population (0.5μg/mL– 5μg/mL). But when the two factors were combined, the median VCZ-Ctrough was steadily increasing as the metabolic capacity (reflected by combined total score) was increasing. Importantly, the median VCZ-Ctrough in PM/PPIs user (total score 5) was significantly elevated to supra-therapeutic levels compared to NM/PPI non-user group (total score 2) (5.83μg/mL [IQR, 2.19μg/mL– 9.51μg/mL] versus 1.13μg/mL [IQR, 0.67μg/mL– 1.82μg/mL]), respectively, P < 0.0001. Furthermore, we observed that the elevation of median VCZ-Ctrough to supra-therapeutic levels was largely contributed by omeprazole or esomeprazole compared to lansoprazole or pantoprazole.Conclusion: Coadministration with PPIs significantly increased voriconazole trough concentrations and there was an additive effect in CYP2C19 PMs, who were most likely to have supra-therapeutic levels.Keywords: voriconazole, proton pump inhibitors, CYP2C19 polymorphism, drug–drug interaction, drug–disease interaction
