Andrzej Bienczak, MPharm, MSc (1), Adrian Cook, MSc (2), Lubbe Wiesner, PhD (1), Maxwell T. Chirehwa, MSc (1), Sarah Walker, PhD (2), Andrew Owen, PhD (3), Diana Gibb, MD, PhD (2), David Burger, PharmD, PhD (4), Helen McIlleon, PhD (1), Paolo Denti, PhD (1) and CHAPAS1/CHAPAS3 Study Teams
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; (2) MRC Clinical Trials Unit, London, United Kingdom; (3) Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom; (4) Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
Objective: To develop a pharmacokinetic (PK) model of nevirapine (NVP) in African children accounting for the effect of CYP2B6 polymorphisms and diurnal variation on clearance (CL) and 1st-pass metabolism.
Methods: Data were included from children from CHAPAS 1 and 3 studies [1,2] (n=420, age 0.25-15 years) treated with NVP solid fixed-dose formulations BD according to WHO recommendations.[3,4]
NONMEM 7.3 was used to implement a semi-mechanistic well-stirred hepatic model [5]. Allometric scaling was applied to all CL and volume parameters.[6] The effect of diurnal variation and maturation were tested on intrinsic CL (CLint) and pre-hepatic bioavailability (F).[7-9] Mixture modelling was used to impute missing genotypes (n=96).[10]
Simulations were used to evaluate the effect of genotype, intake time (6:00, 7:00, 8:00, 9:00 AM/PM), and dose-splitting strategies (AM/PM – D1:100/50 mg, D2:75/75 mg, D3:50/100 mg) on Cmin and AUC.
Results: NVP PK was best described using a 1-cmpt disposition model with absorption through 2 transit cmpts[11] and elimination using hepatic extraction accounting for 1st -pass effect. NVP free fraction was assumed to be 0.4 [12] and hepatic plasma flow 50 L/h in a 70 kg person [13]. Four metaboliser groups determined by 516G>T|983T>C genotypes had the following CLint (ref. WT 14.5 kg): extensive (EM) 3.27 L/h, intermediate (IM) 2.72, slow (SM) 1.65 and ultra-slow (USM) 1.04. Diurnal variation in CLint was best described using a cosine function with peak amplitude of 29.2% at 12 PM. No effect of maturation on CLint was detected, but age-driven differences in pre-hepatic F were found and described using an exponential model with F at birth = 58.3% and t1/2F = 0.64 year.
Simulations showed that depending on intake time the ratio between median Cmin AM/PM was 1.09–1.15 and AUC 1.03–1.07. The differences in ratios between median Cmin AM/PM for tested dose-splitting strategies were: D1 0.93, D2 1.13, D3 1.41; and AUC: 0.90, 1.04, and 1.22, respectively. Cmin_PM <3mg/L [14] was observed in 43% of EM min_PM >7.6 mg/L.[14]
Conclusions: Simulations suggest that average Cmin and AUC in NVP are not greatly affected by intake time, possibly due to long t1/2. When dose cannot be split equally, larger doses should be given AM. To achieve homogenous exposures, the NVP dose for SM and USM should be reduced by 50%. Children
References:
[1] Mulenga, V. et al. Strategies for Nevirapine Initiation in HIV-Infected Children Taking Pediatric Fixed Dose Combination ‘Baby Pills’ in Zambia: A Randomized Controlled Trial. Clin. Infect. Dis. 51, 1081–1089 (2010).
[2] Mulenga, V. et al. Abacavir , zidovudine , or stavudine as paediatric tablets for African HIV-infected children ( CHAPAS-3 ): an open-label , parallel-group , randomised controlled trial. Lancet Infect. Dis. 3099, 1–11 (2015).
[3] World Health Organisation. Antiretroviral therapy for HIV infection in infants and children: Towards universal access. (2010). at http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf
[4] World Health Organisation. WHO recommendations on ARV medicines for treating and preventing HIV infections in younger children, technical summary. 30 Nov 2006. (2006). at http://www.who.int/hiv/paediatric/technicalsummary113006.pdf
[5] Gordi, T. et al. A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction. Br. J. Clin. Pharmacol. 59, 189–98 (2005)
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[9] van Rongen, a et al. Population Pharmacokinetic Model Characterizing 24-Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers. CPT Pharmacometrics Syst. Pharmacol. 4, 454–464 (2015).
[10] 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).
[11] 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).
[12] Boehringer Ingelheim International GmbH. SUMMARY OF PRODUCT CHARACTERISTICS – Viramune.
[13] Bradley, S., Ingelfinger, F., Bradley, G. & Curry, J. The Estimation of Hepatic Blood Flow in Man. J Clin Inves 24, 890–897 (1945).
[14] La Porte, C. J. L. et al. Updated guideline to perform therapeutic drug monitoring for antiretroviral agents. Rev. Antivir. Ther. 3, 5–14 (2006).
Reference: PAGE 25 () Abstr 5765 [www.page-meeting.org/?abstract=5765]
Poster: Drug/Disease modeling - Paediatrics