Silke E. München (1), Stephanie Pieper (2), Uwe Kirchhefer (3), Carsten Müller (4), Judith Moskovits (5), Thomas Lehrnbecher (5), Andreas H. Groll (2), Georg Hempel (1)
(1) Department of Pharmaceutical and Medicinal Chemistry, Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Germany, (2) Department of Pediatric Hematology/Oncology, University Children’s Hospital, Münster, Germany, (3) Institute of Pharmacology and Toxicology, Westfälische Wilhelms-Universität Münster, Germany, (4) Division of Therapeutic Drug Monitoring, Department of Pharmacology University Hospital of Cologne, Germany, (5) Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe-University, Frankfurt, Germany
Objectives: In order to predict new dosing regimens to receive more sustainable trough concentrations in the supposed range of 1 – 6 mg/L, a population pharmacokinetic model for voriconazole including children younger than two years old was developed.
Methods: Plasma concentrations were obtained from an open-label study on PK in 24 paediatric patients (0.5 to 21 years) receiving both i.v. and oral voriconazole as prophylactic treatment. Non-linear mixed effects modelling (NONMEM 7.2) was used to develop the pharmacokinetic model based on the model developed by Friberg et al. [1].
Model diagnostic plots were performed using R in combination with the Xpose package. The final model was evaluated internal and externally. Subsequently Monte – Carlo Simulations were performed to test different dosing regimens.
Results: A two compartment model with first order absorption and non-linear Michaelis-Menten elimination was found to most adequately describe the pharmacokinetics of voriconazole (VMAX=61.6 mg/h/70kg, V1=237 L/70kg, Q=23.5 L/h/70kg, V2=685 L/70kg, F= 61.7 %, Km = fixed to 1.15 mg/L, Ka = fixed to 1.19 h-1). Inter‑individual variability on VMAX (67.7%), V1 (74.2%), Q (51.2%) and F (60% as logistic transformation) and residual variability (proportional error 15.6%, additive error 0.013 mg/L) were assessed. Allometric scaling with a fixed exponent of 0.75 on body weight for VMAX and Q, and body weight on V1 and V2 was used.
A three times per day (TID) regimen with a loading dose of 9mg/kg TID followed by 6mg/kg TID maintenance dosing from day 2 onward was simulated resulting in an increase in the percentage of patients attaining the target trough concentration above 1mg/L after 24h from 9% to 43% relative to the currently recommended dosing of 9mg/kg BID on day 1 followed by 8mg/kg BID maintenance dosing.
Measured trough concentrations after 120h resulted in 42.4% patients reaching the target trough concentration for the currently recommended BID dosing. The TID regimen with an initial loading dose for 24h, 48h and 72h resulted in 54.5%, 57.2% and 61% adequately treated patients, respectively.
Conclusions: Voriconazole pharmacokinetics is highly variable and therapeutic drug monitoring is recommended. With our simulated TID regimen, more patients reached adequate trough concentrations in the first 24h of treatment. In the further course of treatment, the difference in adequately dosed patients was lower.
References:
[1] Friberg LE, Ravva P, Karlsson MO, Liu P. Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults. Antimicrob. Agents Chemother. (2012) 56(6):3032-3042
Reference: PAGE 25 (2016) Abstr 5870 [www.page-meeting.org/?abstract=5870]
Poster: Drug/Disease modeling - Paediatrics