Jaeseong Oh (1), Su-jin Rhee (1), SeungHwan Lee (1), Juyoung Lee (2), Kyungho Jang (1), Seonghae Yoon (1), Kyung-Sang Yu (1), In-Jin Jang (1), Han-Suk Kim (2)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; (2) Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
Objectives: Fluconazole prophylaxis is an efficacious therapeutic strategy to reduce invasive candidiasis mortality rates in premature infants with extremely low birth weight. However, the pharmacokinetic (PK) data of fluconazole in premature infants are limited to guide dosing. The aim of this study was to develop a population PK model for fluconazole in premature infants.
Methods: A total of 301 fluconazole plasma concentrations from 75 premature infants (post-natal age 3-8 days, post-menstrual age (PMA) 21.3-35.7 weeks, body weight (WT) 0.54-1.49 kg) who admitted neonatal intensive care unit of Seoul National University Children’s Hospital were pooled to develop a population PK model using the nonlinear mixed-effects method in NONMEM (ver. 7.3). Subjects received intravenous (30 min infusion) or oral 3 mg/kg dose of fluconazole, with more than 72 hours dose interval. The First-Order Conditional Estimation with Interaction estimation method was implemented, which was followed by model qualification using bootstrapping and visual predictive checks (VPCs).
Results: A one-compartment linear PK model with proportional residual error was chosen as the final PK model. The population mean clearance (CL) and volume of distribution (V) was derived by the following equations: CL (L/h) equals 0.0214 ∙ (WT) 0.75 ∙ (PMA/30)0.468 ∙ (serum creatinine/0.5)-0.412; V (L) equals 1.06 ∙ (WT). The inter-individual variability of CL and V were 24%, 20.7%. The oral bioavailability of fluconazole was 91%. Model evaluation by bootstrapping and VPCs suggested that the proposed model was adequate and robust with good precision.
Conclusions: The final PK model of fluconazole adequately described the observed plasma concentration of fluconazole in premature infants. The model-fitted parameter estimates may be applied to determine the optimal dosage regimens of fluconazole in premature infants.
Reference: PAGE 24 (2015) Abstr 3462 [www.page-meeting.org/?abstract=3462]
Poster: Drug/Disease modeling - Paediatrics