Yu Kyong Kim (1), Jaeseong Oh (1), Su-jin Rhee (1), SeungHwan Lee (1), In-Jin Jang (1), Kyung-Sang Yu (1)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Objectives: Several reports have been suggested that prophylactic use of antifungal agents such as fluconazole reduces mortality rate in preterm infants with extremely low birth weights via suppression of invasive systemic candidiasis causing Candida colonization [1]. However, the human data for appropriate prophylactic dosage regimen of fluconazole in preterm infants are limited; hence the off-label uses based upon empirical knowledge of the paediatricians. This study was to construct a population pharmacokinetic model for prophylactic fluconazole in Korean preterm infants for suggestion of optimal dosage regimen.
Methods: By using a nonlinear mixed-effects method in NONMEM (version 7.4) [2] a population pharmacokinetic model was developed using the prospectively collected 301 fluconazole plasma concentrations from 75 premature infants (post-natal age range of 3-8 days, gestational age of 23.7-35.7 weeks and body weight of 0.54-1.49 kg) who admitted to the neonatal intensive care unit of Seoul National University Children’s Hospital. Eligible premature infants received intravenous (30 min infusion) or oral 3 mg/kg dose of fluconazole, twice weekly with more than 72-hour dose interval, for 4 weeks. Implementing the First-Order Conditional Estimation with Interaction estimation method, the model was sequentially qualified with basic goodness-of-fit (GOF) diagnostics, visual predictive checks (VPCs) and bootstrapping for evaluation of adequacy and prediction. Simulations were performed investigating different dosing intervals and dosages for optimum regimen that >90% of the simulated data would result in pre-specified efficacious exposure [3].
Results: Fluconazole pharmacokinetic characteristics were well described with a one-compartment linear pharmacokinetic model with proportional residual error. With the following equations, the population clearance and volume of distribution were derived: clearance (L/h) = 0.0219 ∙ (body weight)0.746 ∙ (estimated glomerular filtration rate with Schwartz equation for infants with low body weight under 1-year-old/25)0.463; volume of distribution (L) = 1.04 ∙ (body weight). The inter-individual variabilities (coefficient of variations, %) of clearance and volume of distribution were 23.8% and 21.4%, respectively. The estimated oral bioavailability of fluconazole was 90.9%. The proposed model was adequate with good precision based on the model evaluation by GOF diagnostics, VPCs, and bootstrapping. The simulated data suggested that at least 6 mg/kg every 24-hour regimen would be necessary to achieve the previously suggested exposure of fluconazole for prophylaxis in preterm infants with glomerular filtration rate range of 10.3 – 46.8 mL/min/1.73m2.
Conclusions: With the final pharmacokinetic model of fluconazole which adequately described the observed plasma concentration of fluconazole in preterm infants, the model-fitted parameter estimates and simulation allowed suggestion of prophylactic fluconazole dosage regimens in preterm infants.
References:
[1] Benjamin Jr DK et al., Effect of Fluconazole Prophylaxis on Candidiasis and Mortality in Premature Infants A Randomized Clinical Trial Journal of American Medical Association 2014;311(17):1742-49
[2] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2017. Icon Development Solutions, Gaithersburg, Maryland, USA.
[3] Wade KC et al., Fluconazole Dosing for the Prevention or Treatment of Invasive Candidiasis in Young Infants 2009;28(8):717-23
Reference: PAGE 27 (2018) Abstr 8436 [www.page-meeting.org/?abstract=8436]
Poster: Drug/Disease Modelling - Paediatrics