Antimicrob Agents Chemother. 2020 Sep 28;:
Authors: Takahashi T, Smith AR, Jacobson PA, Fisher J, Rubin NT, Kirstein MN
Abstract
BACKGROUND: Voriconazole (VCZ) is an antifungal agent with wide inter- and intra- patient pharmacokinetic (PK) variability and narrow therapeutic index. Although obesity was associated with higher VCZ trough concentrations in adults, the impact of obesity is yet to be studied in children. We characterized the PK of VCZ in obese accounting for age and CYP2C19 phenotype.
METHODS: We conducted intensive PK studies of VCZ and VCZ N-oxide metabolite in 44 hematopoietic stem cell transplant (HSCT) recipients aged 2-21 years who received prophylactic intravenous VCZ q12h. Blood samples were collected at 5 and 30 minutes; 1, 3, 6 and 9 hours after infusion completion; and immediately before the next infusion start. We estimated PK parameters with non-compartmental analysis and evaluated for association with obesity by multiple linear regression analysis.
RESULTS: The 44 participants included 9 (20%) with obesity. CYP2C19 metabolism phenotypes were identified as normal in 22 (50%), poor/intermediate in 13 (30%), and rapid/ultra-rapid in 9 patients (21%). Obesity status significantly affects VCZ Cmin (higher by 1.4 mg/L, 95%CI: 0.0-2.8, p = 0.047) and VCZ AUCRATIO (higher by 0.4; 95%CI: 0.0-0.7; p=0.03) while no association was observed with VCZ AUC (p=0.09) after adjusting for clinical factors. A younger age and a CYP2C19 phenotype were associated with lower VCZ AUC.
CONCLUSION: Obesity was associated with decreased metabolism of VCZ to its inactive N-oxide metabolite and, concurrently, increased VCZ Cmin, which is deemed clinically meaningful. Future research should aim to further characterize its effects and determine a proper dosing regimen for the obese.
PMID: 32988816 [PubMed - as supplied by publisher]
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