Impact of Obesity on Voriconazole Pharmacokinetics among Pediatric Hematopoietic Cell Transplant Recipients

Voriconazole (VCZ) is an antifungal agent with wide inter- and intrapatient pharmacokinetic (PK) variability and narrow therapeutic index. Although obesity was associated with higher VCZ trough concentrations in adults, the impact of obesity had yet to be studied in children. We characterized the PK of VCZ in obese patients by accounting for age and CYP2C19 phenotype. We conducted intensive PK studies of VCZ and VCZ N-oxide metabolite in 44 hematopoietic stem cell transplantation (HSCT) recipients aged 2 to 21 years who received prophylactic intravenous VCZ every 12 hours (q12h). Blood samples were collected at 5 and 30 minutes; at 1, 3, 6, and 9 hours after infusion completion; and immediately before the next infusion start. We estimated PK parameters with noncompartmental analysis and evaluated for an association with obesity by multiple linear regression analysis. 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/ultrarapid in 9 patients (21%). Obesity status significantly affects the VCZ minimum concentration of drug in serum (C_min) (higher by 1.4 mg/liter; 95% confidence interval [CI], 0.0 to 2.8; P= 0.047) and VCZ metabolism ratio (VCZ_RATIO) (higher by 0.4; 95% CI, 0.0 to 0.7; P= 0.03), while no association was observed with VCZ area under the curve (AUC) (P= 0.09) after adjusting for clinical factors. A younger age and a CYP2C19 phenotype were associated with lower VCZ AUC. Obesity was associated with decreased metabolism of VCZ to its inactive N-oxide metabolite and, concurrently, increased VCZ C_min, which is deemed clinically meaningful. Future research should aim to further characterize its effects and determine a proper dosing regimen for the obese.