Effect of proton pump inhibitor on plasma voriconazole concentration in Thai patients.
BACKGROUND
Voriconazole is an antifungal drug used for treatment of invasive aspergillosis. It is metabolized mainly via the cytochrome P450 isoenzymes CYP2C19, through which its enzymatic activity can be inhibited by proton pump inhibitors (PPI), especially omeprazole. Previous reports demonstrated that omeprazole might be used to boost plasma voriconazole levels in infected patients. However; there was no difference in plasma voriconazole concentration in healthy individuals, who received omeprazole versus placebo. Therefore, the interaction between PPI and voriconazole may be different between healthy and infected individuals.


OBJECTIVE
To determine the effects of omeprazole on plasma voriconazole concentration in Thai patients who had invasive fungal diseases.


METHODS
The present study is a prospective observational study and is a sub-study of the voriconazole therapeutic drug monitoring study. Patients treated with voriconazole admitted at Siriraj Hospital during July 2011 to September 2013 were enrolled. Blood samples were drawn for plasma voriconazole concentration assays at day 0, 3, 7, 14 and 28. Data regarding PPI use were collected and analyzed in correlation with plasma voriconazole concentration.


RESULTS
Of 54 patients enrolled, 47 had sufficient clinical data but 46 patients had complete data of voriconazole levels. Patients mean age was 47 years and 60% were male. Thirty-nine patients (83%) had invasive pulmonary aspergillosis. Forty-one patients (87.2%) received PPI, among which 37 (90.2%) were omeprazole. Patients with PPI use had no difference in plasma voriconazole concentration, when compared with those without PPI use, at day 3 (5.89 vs. 5.44 mg/L, p = 0.744), day 7 (5.4 vs. 5.29 mg/L, p = 0.471), day 14 (2.40 vs. 3.13 mg/L, p = 0.372) and day 28 (1.77 vs. 3.23 mg/L, p = 0.314). Although there was a trend toward higher plasma voriconazole concentration in patients receiving higher omeprazole dose (> 20 mg/day), the difference between those treated with high (> 20 mg/day) and low (20 mg/day) doses of omeprazole was not statistically significant at day 3 (6.27 vs. 4.87 mg/L, p = 0.429), day 7 (7.44 vs. 3.78 mg/L, p = 0.166), day 14 (2.52 vs. 1.68 mg/L, p = 0.534) and day 28 (2.51 vs. 1.44 mg/L, p = 0.154). Similarly, the duration of omeprazole use in concurrent with voriconazole treatment was not associated with plasma voriconazole concentration in infected patients.


CONCLUSIONS
Omeprazole does not affect plasma voriconazole concentration in infected patients. However, patients who received higher doses ofomeprazole (> 20 mg/day) tend to have a higher concentrations of plasma voriconazole.
Methee
M
Chayakulkeeree
Natthanan
N
Poovipirom
Pimkamon
P
Siengwattana
Monthira
M
Maneerattanaporn
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy*; D009853:Omeprazole / Q000008:administration & dosage / Q000494:pharmacology*; D011446:Prospective Studies; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013785:Thailand; D065819:Voriconazole / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
D000935:Antifungal Agents; D054328:Proton Pump Inhibitors; D065819:Voriconazole; D009853:Omeprazole