Andrzej Bienczak, MPharm, MSc (1), Quirine Fillekes, PhD (2) , Helen McIlleron, MBChB, PhD (1), Diana Gibb, MD, PhD (3), David Burger, PharmD, PhD (2), Paolo Denti, PhD (1)
(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) MRC Clinical Trials Unit, London, United Kingdom;
Objectives: The aim of this project was to characterise efavirenz at steady state in African children and to evaluate the use of mixture modelling to account for multimodal clearance, as an alternative, in the absence of individual CYP2B6 genotype data.
Methods: We analysed intensive data from following studies: ARROW (n=41, age 4-12) and CHAPAS3 (n=51, age 3-13). Both studies took place at multiple sites in Uganda and Zambia and plasma concentrations of efavirenz were quantified using validated LC/MS/MS method.
Model building was conducted using NONMEM 7.2 (FOCE-I). A number of subroutines and structural models and previously published approaches were evaluated1,2. Model building was guided by differences in OFV, VPCs and other diagnostic plots.
Results: In total 995 sample concentrations were included in the analysis: 15% were below 1µg/ml (n=150), 29% were above 4µg/ml (n=288), and 56% were within the therapeutic range (n=577)3.
The data was best described using a 2-compartment model with absorption through a number of transit compartments 4. BSV was set on central and inter-compartmental clearances, and volume of central and peripheral compartments. BOV was set on bioavailability, mean transit time and absorption rate constant. Allometric scaling was used to account for effect of size5 and typical values were estimated for an 18.5 kg child. The multimodal distribution of CL due to CYP2B6 polymorphisms was described using a mixture model. Three subpopulations were identified: extensive metabolisers (60% of the children) – 7.05 L/h, intermediate (25%) – 2.81 L/h, and slow (15%) -1.87 L/h. The model did not identify a significant effect of clearance maturation.
Conclusions: The model adequately describes the data and the mixture model significantly improved the fit. This multimodality for efavirenz clearance is consistent with previous reports, although the typical values and frequency of each subgroup found in this analysis differ from previous publications7,8. This may be due to the fact that in mixture modelling approach those values are estimated empirically based on the data and not on the robust information about genotype, and may be affected by other confounders. The lack of a maturation effect could be due to the fact that all children in the study were older than 3 years. In order to improve stability of the model and characterise other sources of variability incorporation of information on patients’ genotype is needed.
References:
[1]. Mould, D. R. & Upton, R. N. Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT pharmacometrics Syst. Pharmacol. 2, e38 (2013).
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[3]. Marzolini, C. et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 15, 71–5 (2001).
[4]. 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).
[5]. Holford, N., Heo, Y. & Anderson, B. A Pharmacokinetic Standard for Babies and Adults. J. Pharm. Sci. 102, 2941–2952 (2013).
[6]. Holzinger, E. R. et al. Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants. Pharmacogenet. Genomics 22, 858–67 (2012).
[7]. Viljoen, M. et al. 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, 339–47 (2012).
[8]. Saitoh, A. et al. Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism. J. Acquir. Immune Defic. Syndr. 45, 280–5 (2007).
Reference: PAGE 23 (2014) Abstr 3230 [www.page-meeting.org/?abstract=3230]
Poster: Drug/Disease modeling - Infection