Tjokosela Tikiso (1), Helena Rabie (2), Helen McIlleron (1), Janice Lee (3), Isabelle Andrieux-Meyer (3), Mark Cotton (2), Marc Lallemant (3), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine University of Cape Town, (2) Department of Pediatrics and Child Health and Children’s Infectious Clinical research Unit University of Stellenbosch and Tygerberg Hospital, (3) Drugs for Neglected Diseases initiative
Objectives: Co-treatment of HIV and tuberculosis in infants and young children is unavoidable in much of Africa, increasing risks for drug-drug interactions (1). More data is needed to characterise drug interactions to better manage children of various ages. No data is available on the pharmacokinetics and efficacy of abacavir when co-administered with rifampicin-based tuberculosis treatment and super-boosted lopinavir (LPV/r plus additional ritonavir). Our objective is to compare pharmacokinetics of abacavir during treatment with standard doses of LPV/r vs. anti-TB treatment and super-boosted lopinavir.
Methods: 87 TB/HIV-infected South African children (median age: 2.8, range 0.25-6 years; weight: 9.4, 4-16 kg) were sampled on 3 separate visits: (a) after at least 2 weeks on TB treatment and super-boosted lopinavir during the intensive phase and (b) at the end of the continuation phase of TB treatment; and (c) one month after TB treatment completion on standard doses of LPV/r dose without additional ritonavir. Abacavir twice-daily was co-administered throughout. All drugs were dosed according to the South African weight-band dosing recommendations. At each visit, blood samples were collected immediately before dosing and 1, 2, 4, 6, 8, and 10 hours thereafter. NONMEM 7.3 with FOCE-I was used to develop a population pharmacokinetic model. PsN, Pirana and Xpose were used to facilitate modelling and model diagnostics (2). Allometric scaling (3) 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 maturation (4) 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, as outlined in the method M6 by Beal et al (5).
Results: Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination and transit compartment absorption. Allometric scaling was used to adjust for the effect of body size, after which maturation could be identified: clearance was predicted to reach half its mature value at around 2 months after birth and to be fully mature by around 2 years of age. The typical clearance in a 9-kg child co-treated with normal dose LPV/r is estimated at 8.8 L/h. During co-administration of TB treatment with lopinavir super-boosting, a 38% decrease in bioavailability was found. Finally, the trough concentrations observed just before the morning dose were higher than the extrapolated values predicted 12 h after a morning dose, and this was best explained by including a 24% reduction in clearance overnight.
Conclusions: The proposed model successfully characterised the PK of abacavir, including the effect of body weight and age. Abacavir exposure was significantly decreased by concomitant administration of rifampicin and super-boosted lopinavir. Larger trough concentrations were observed in the morning, possibly indicating circadian variation in the pharmacokinetics. Although 67 (82%) children were virologically suppressed at the end of TB treatment compared to 6 (6%) at study entry, further investigation should address whether dosing adjustments are necessary to counteract the effect of the drug-drug interaction.
References:
[1] Johnson LF, Davies MA, Moultrie H, Sherman GG, Bland RM, Rehle TM, Dorrington RE, Newell ML. The Effect of Early Initiation of Antiretroviral Treatment in Infants on Pediatric AIDS Mortality in South Africa: A Model-based Analysis. Pediatr Infect Dis J. 2012; (5):474-480.
[2] Keizer, R. J., Karlsson, M. O., & Hooker, A. (2013). Modeling and Simulation Workbench for NONMEM: Tutorial on Pirana, PsN, and Xpose. CPT: Pharmacometrics & Systems Pharmacology, 2(6), e50.
[3] Anderson, B. J., & Holford, N. H. G. (2008). Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics. Annual Review of Pharmacology and Toxicology, 48(1), 303–332.
[4] Anderson, B. J., & Holford, N. H. G. (2013). Understanding dosing: children are small adults, neonates are immature children. Archives of Disease in Childhood, 98(9), 737–44.
[5] Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn [Internet]. 2001 Oct;28(5):481–504. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11768292
Reference: PAGE 27 (2018) Abstr 8702 [www.page-meeting.org/?abstract=8702]
Poster: Drug/Disease Modelling - Infection