Tjokosela Tikiso (1), Helen McIlleron (1), Helena Rabie (2), Janice Lee (3), Moherndran Archary (4), Stefanie Hennig (5), Mark Cotton (2), Marc Lallemant (3), Diana Gibb (6), David Burger (7), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa, (2) Department of Paediatrics and Child Health and Family Centre for Research with Ubuntu (FAM-CRU), Stellenbosch University and Tygerberg Children’s Hospital, (3) Drugs for Neglected Diseases initiative, (4) Department of Paediatrics and Child Health at King Edward VIII Hospital affiliated to the Nelson R Mandela School of Medicine, University of KwaZulu-Natal, (5) School of Pharmacy, University of Queensland, Brisbane, Australia, (6) MRC Clinical Trials Unit at University College London, London, United Kingdom, (7) Department of Pharmacy, Radboud University Medical Centre, Nijmegen, the Netherlands.
Objectives: Abacavir given together with other antiretrovirals (ARV) such as efavirenz, lamivudine and lopinavir/ritonavir (4:1) are recommended as a component of 1st line antiretroviral treatment (ART) for infants and children below 12 years1. HIV is complicated by many conditions such as malnutrition and tuberculosis (TB) which require concomitant treatment and can potentially lead to drug-drug interaction. Abacavir is primarily metabolized by uridine diphosphate glucuronyltransferase and alcohol dehydrogenase, it is also a P-glycoprotein substrate. Knowledge of abacavir pharmacokinetics in children is limited. More data is required to characterise the impact of covariates on the pharmacokinetics of abacavir to better guide the management of children of various ages. Our objective is to conduct an in-depth population pharmacokinetics of abacavir to better characterize the differences in demographics, concomitant co-medications and other covariates.
Methods: A total of 229 HIV-infected African children from the studies ARROW2 (n=41), CHAPAS3 (n=29), DNDI4 (n=84), and MATCH5 (n=75) were used for pooled modelling analysis. The median age and weight of the pooled data was 0.79 (range, 0.14-12.78) years and 6.08 (range,2.5-30) kg respectively. The studies all included intensively sampled profiles on separate visits. Of the 229 children available for analysis, 183 were dosed twice daily while 46 were on daily dosing. 155 children were on concomitant lopinavir/ritonavir and 79 were on efavirenz. One hundred and six children received rifampicin-containing anti-TB treatment. Of these, 103 were on super-boosted lopinavir/ritonavir (1:1) and 3 on efavirenz. From the 229 children, 156 were malnourished, with weight-for-age z-score and height-for-age z-score below -2.0. Due to the combination of studies, the distributions of the covariates were unbalanced. NONMEM 7.4.3 with FOCE-I was used to develop a population pharmacokinetic model. PsN, Pirana and Xpose were used to facilitate modelling and model diagnostics6. Allometric scaling7 was used to account for the effect of body size, using different predictors such as fat-free mass (FFM), fat mass and total weight. The effect of maturation8 on clearance was tested as a potential covariate. Data below the limit of quantification was imputed with half the value of low limit of quantification, and only the first values in a series was retained in the analysis according to method M6 9.
Results: Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination and transit compartment absorption. Allometric scaling with total body weight adjusted well for the effect of body size, after which maturation could be identified: clearance was predicted to reach half its mature value at around 3 months after birth and to be fully mature by around 2 years of age. The typical clearance in a child weighing 11-kg and co-treated with normal dose LPV/r (4:1) was estimated at 10.9 L/h. During co-administration of anti-TB treatment with lopinavir super-boosting (LPV/r 1:1), a 33% decrease in bioavailability was found. A decreased clearance was observed in the malnourished HIV–infected children. Also, the first visit in MATCH (first-dose), had larger exposures due to lower clearance.
Conclusions: The proposed model successfully characterised the abacavir PK, including the effect of body weight and age. Abacavir exposure was significantly decreased by concomitant administration of rifampicin and super-boosted lopinavir. Clearance was significantly decreased in malnourished HIV-infected children. Exposure on the first dose was larger, possibly pointing towards induction of clearance over time on ART. Further investigation should address whether dosing adjustments are necessary to counteract the effect of drug-drug interaction and malnutrition.
References:
[1] Who, Unicef. Antiretroviral therapy for HIV infection in infants and children: Towards universal access. Annex E: Prescribing information and weight-based dosing of available ARV formulations for infants and children.
[2] Musiime V, Kasirye P, Naidoo-James B, et al. Once vs twice-daily abacavir and lamivudine in African children. AIDS. 2016;30(11):1761-1770.
[3] Mulenga V, Musiime V, Kekitiinwa A, 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. 2016;16(2):169-179.
[4] Rabie H, Denti P, Lee J, et al. Lopinavir-ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study. lancet HIV. 2018;6(1):e32-e42. doi:10.1016/S2352-3018(18)30293-5.
[5] Archary M, Mcllleron H, Bobat R, et al. Population Pharmacokinetics of Lopinavir in Severely Malnourished HIV Infected Children and the Effect on Treatment Outcomes. Pediatr Infect Dis J. 2017;37(4):1.
[6] Keizer RJ, Karlsson MO, Hooker A. Modeling and Simulation Workbench for NONMEM: Tutorial on Pirana, PsN, and Xpose. CPT pharmacometrics Syst Pharmacol. 2013;2(6):e50. doi:10.1038/psp.2013.24.
[7] Anderson BJ, Holford NHG. Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48(1):303-332. doi:10.1146/annurev.pharmtox.48.113006.094708.
[8] Anderson BJ, Holford NHG. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child. 2013;98(9):737-744. doi:10.1136/archdischild-2013-303720.
[9] Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28(5):481-504. http://www.ncbi.nlm.nih.gov/pubmed/11768292. Accessed February 23, 2018.
Reference: PAGE 28 (2019) Abstr 9165 [www.page-meeting.org/?abstract=9165]
Poster: Drug/Disease Modelling - Infection