| Popis: |
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 mmafuru@gmail.com; magesa.mafuru@hkmu.ac.tzPurpose: 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 |
