Population Pharmacokinetics of Liposomal Amphotericin B in Pediatric Patients with Malignant Diseases

Abstract

ABSTRACT A population pharmacokinetic model of liposomal amphotericin B (L-AmB) in pediatric patients with malignant diseases was developed and evaluated. Blood samples were collected from 39 pediatric oncology patients who received multiple doses of L-AmB with a dose range from 0.8 to 5.9 mg/kg of body weight/day. The patient cohort had an average age of 7 years (range, 0.2 to 17 years) and weighed an average of 28.8 ± 19.8 kg. Population pharmacokinetic analyses were performed with NONMEM software. Pharmacokinetic parameters, interindividual variability (IIV), between-occasion variability (BOV), and intraindividual variability were estimated. The influence of patient characteristics on the pharmacokinetics of L-AmB was explored. The final population pharmacokinetic model was evaluated by using a bootstrap sampling technique. The L-AmB plasma concentration-time data was described by a two-compartment pharmacokinetic model with zero-order input and first-order elimination. The population mean estimates of clearance (CL) and volume of distribution in the central compartment ( V 1 ) were 0.44 liters/h and 3.12 liters, respectively, and exhibited IIV (CL, 10%) and significant BOV (CL, 46% and V 1 , 56%). The covariate models were CL (liters/h) = 0.44 · e 0.0152 · (WT − 21 ) and V 1 (liters) = 3.12 · e 0.0241  ·  (WT   −   21) , where WT is the patient's body weight (kg) centered on the study population cohort median of 21 kg. Model evaluation by the bootstrap procedure indicated that the full pharmacokinetic model was robust and parameter estimates were accurate. In conclusion, the pharmacokinetics of L-AmB in pediatric oncology patients were adequately described by the developed population model. The model has been evaluated and can be used in the design of rational dosing strategies for L-AmB antifungal therapy in this special population.