Simbarashe Peter Zvada [1], Sherwin Sy [2], Nikolaus Bauer [3], Mirjam von Bibra [3], Daniel Clemens [3], Hartwig Klinker [3], Hartmut Derendorf [2], Bernd Rosenkranz [1]
[1] Division of Clinical Pharmacology, Stellenbosch University, South Africa, [2] Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA, [3] Department of Internal Medicine II, Center of Infectious Diseases, University of Würzburg Medical Center, Würzburg, Germany
Background and objectives: Efavirenz is widely used for the treatment of HIV in children and adults, including pregnant women. The existing population pharmacokinetic models of efavirenz in the literature do not include clinical data from children, adults and pregnant women. The aim of this study was to develop a model that describes the population pharmacokinetics of efavirenz in children and adults including pregnant women, and to investigate factors which may alter the pharmacokinetics of efavirenz.
Methods: Clinical data and efavirenz concentration-time data were obtained from a prospective, open label, uncontrolled study which comprised of HIV-positive adults (N=271), children (N=48) and pregnant women (N=63) in South Africa. Sparse blood sampling, consisting of one sample per patient, was conducted in patients who are already at steady state. A validated high performance liquid chromatography method was used to determine efavirenz serum levels. NONMEM 7.3 was used for the population pharmacokinetic modelling of efavirenz. Previously published efavirenz model supplied the prior pharmacokinetic information [1] required for a full Markov Chain Monte Carlo Bayesian (MCMCB) analysis; FOCE-I algorithm also utilized prior information. Body weight was included through allometric scaling on clearance and volume parameters. A mixture model with 3 subpopulations was used to group the drug-metabolism phenotypes of these patients.
Results: The population pharmacokinetics of efavirenz was best described by a one compartment model with first-order absorption and elimination. Interindividual variability was incorporated in the oral clearance and volume of distribution. The estimates of FOCE-I were almost identical to MCMCB; the former was preferred due to shorter computational time. The clearances were 6.3, 10.1 and 16.0 L/hr for the slow, intermediate and fast metabolisers with approximately 50% of the adults grouped as rapid metaboliser and the majority from this group being females. No other covariates were identified.
Conclusions: Our model adequately described the population pharmacokinetics of efavirenz in children and adults, including pregnant women. Adults are at risk of low levels of efavirenz with females being at a higher risk. The model developed in this study could be used to simulate relevant doses of efavirenz and can potentially be used in therapeutic drug monitoring scenarios.
References:
[1] Viljoen M, Karlsson MO, Meyers TM, Gous H, Dandara C, Rheeders M (2012) Influence of CYP2B6 516G>T polymorphism and interoccasion variability (IOV) on the population pharmacokinetics of efavirenz in HIV-infected South African children. Eur J Clin Pharmacol, 68:339-347
Reference: PAGE 24 (2015) Abstr 3647 [www.page-meeting.org/?abstract=3647]
Poster: Drug/Disease modeling - Infection