Andrzej Bienczak (1), Sandra Castel (1), Quirine Fillekes (2), Lubbe Wiesner (1), Andrew Owen (3), Sarah Walker (4), Diana Gibb (4), David Burger (2), Helen McIlleron (1), Paolo Denti (1) and CHAPAS1/CHAPAS3 Study Teams
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; (2) Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; (3) Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom (4) MRC Clinical Trials Unit, London, United Kingdom;
Objectives: Nevirapine is a NNRTI widely used for treatment of HIV-infected adults and children. It is metabolised by CYP3A4 and CYP2B6 [1]. CYP2B6 polymorphisms significantly influence the disposition of the drug and their prevalence differs between populations [2].
The aim was to characterise the pharmacokinetics (PK) of nevirapine in African children and to identify patient characteristics influencing its disposition.
Methods: Data were pooled from two clinical trials in HIV positive children at four sites in Uganda and Zambia. In the CHAPAS1 study, 7 samples were collected at a single PK visit in 84 children (aged 0.25-15 yrs). In the CHAPAS3 study, 2 samples were collected on 4-7 PK visits, in 334 children (aged 0.45-12.35 yrs) followed longitudinally for 2 years. Concentrations below the lower limit of quantification (LLOQ; 0.0195 mg/L) were imputed as LLOQ/2 [3].
Model building was conducted using NONMEM 7.3 (FOCE-I) following an approach previously suggested to combine intensive and sparse data [4]. Allometric scaling [5] was conducted to account for the effect of body size, and the influence of age and CYP2B6 genotype on CL were investigated.
Model building was guided by differences in objective function value (OFV) and diagnostic plots, including visual predictive checks.
Results: A total of 2989 nevirapine concentrations were included in the analysis and were best described using a 1-compartment model with absorption through a series of transit compartments and first-order elimination [6].
Besides the effect of weight through allometric scaling, the most significant determinant of nevirapine PK was CYP2B6 516|983 genotype on CL [2]. Patients were allocated to 4 metaboliser groups based on their genotype: fast (CL=1.87 L/h, for a 15.4 kg child), intermediate (1.40 L/h), slow (0.87 L/h), and ultra-slow (0.51 L/h). Children with no available genotype information (n=79) were assigned to a group using a mixture model reflecting the prevalence in the rest of the cohort [7].
Including terms to correct for the increased uncertainty in the time of unobserved doses preceding the sparse samples improved fit, leading to an increase in RUV and BOV in bioavailability.
No effect of maturation was detected.
Conclusions: Nevirapine metabolism in children is affected by a composite effect of 2 SNPs in CYP2B6: 516GT (rs3745274) and 983TC (rs28399499). The lack of significance of a maturation effect could be due to small numbers under 2 years of age.
References:
[1] Fan-Havard, P. et al. Pharmacokinetics of phase i nevirapine metabolites following a single dose and at steady state. Antimicrob. Agents Chemother. 57, 2154–2160 (2013).
[2] Haas, D. W. et al. Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African americans. J. Infect. Dis. 199, 872–880 (2009).
[3] Beal, S. L. Ways to fit a PK model with some data below the quantification limit. J. Pharmacokinet. Pharmacodyn. 28, 481–504 (2001).
[4] Svensson, E. et al. Integration of data from multiple sources for simultaneous modelling analysis?: experience from nevirapine population pharmacokinetics. Br. J. Clin. Pharmacol. 74, 465–476 (2012).
[5] Holford, N., Heo, Y. & Anderson, B. A pharmacokinetic standard for babies and adults. J. Pharm. Sci. 102, 2941–2952 (2013).
[6] Savic, R. M., Jonker, D. M., Kerbusch, T. & Karlsson, M. O. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J. Pharmacokinet. Pharmacodyn. 34, 711–26 (2007).
[7] Keizer, R. J., Zandvliet, A. S., Beijnen, J. H., Schellens, J. H. M. & Huitema, A. D. R. Performance of methods for handling missing categorical covariate data in population pharmacokinetic analyses. AAPS J. 14, 601–11 (2012)
Reference: PAGE 24 (2015) Abstr 3633 [www.page-meeting.org/?abstract=3633]
Poster: Drug/Disease modeling - Paediatrics