Population pharmacokinetics of ritonavir-boosted darunavir in children aged 3 to 15 years in the CHAPAS 4 trial living with HIV in Africa.
Lufina Tsirizani Galileya(1,2), Roeland E Wasmann(1), Hylke Waalewijn(1,3), Chishala Chabala(1,4), Lara Monkiewicz(5), Helen McIlleron(1,6), David Burger(3), Diana Gibb(5), Paolo Denti(1), Angela Colbers(3)
(1)Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. (2)Training and Research Unit of Excellence, Kamuzu University of Health Sciences, Blantyre, Malawi. (3)Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands. (4)Department of Pediatrics, University of Zambia, School of Medicine, Lusaka, Zambia. (5)Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, London, United Kingdom. (6)Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Introduction and Objectives: Darunavir is an antiretroviral drug from the class of protease inhibitors (PIs)[1]. It is typically boosted with either ritonavir or cobicistat , CYP3A4 inhibitors which help increase its bioavailability and half-life. In the body, it is 95% bound to plasma proteins, mainly alpha-1-acid glycoprotein (AAG)[1]. Darunavir is generally well tolerated in children[2] but there is a paucity of pharmacokinetic data in this population, especially from low- and middle- income countries, where the highest HIV burden lies[3]. We developed a population PK model of ritonavir-boosted darunavir in children from sub-Saharan Africa, with the aim of investigating the effect of body size, co-administered nucleoside reverse transcriptase inhibitors (NRTIs), protein binding, and ritonavir concentrations on the exposure of darunavir in this population.
Methods: Using non-linear mixed-effects modelling, the population PK of darunavir was characterized with data from the CHAPAS-4 study, a two by four factorial randomized study investigating the PK and acceptability of novel second-line antiretroviral regimens for children in Africa (ISRCTN22964075). Intensive blood samples were collected at week six at 0, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after dose. Darunavir and ritonavir were quantified using LC-MS/MS with a lower limit of quantification of 0.105 mg/L.
One- and two- compartment disposition models with first order absorption, with and without lag time or transit compartments were investigated. We tested first-order elimination with and without first-pass metabolism, or saturable elimination through a liver compartment. Between subject variability (BSV) was included on disposition parameters and between occasion variability (BOV) on absorption parameters. Allometric scaling of clearance (with a fixed exponent of 0.75) and volume (with a fixed exponent of 1) parameters was tested by either weight or fat-free mass[4].
The effect of ritonavir concentrations on darunavir exposure was examined through linear, power, exponential, and Emax relationships as well as a joint model of darunavir and ritonavir, with ritonavir concentrations affecting bioavailability and/or clearance of darunavir through an indirect Emax relationship. The effect of AAG on darunavir clearance was evaluated through linear, power, exponential, or a relationship where darunavir binding to AAG depended on an estimated binding affinity constant (KAFF)[5]. The effect of NRTI backbone as a categorical covariate on darunavir PK was also assessed.
Results: We collected 491 samples (1 below the limit of quantification) from 59 children (66% female). Median (range) weight and age was 26.0 (14.5-47.0) kg, and 10.9 (3.8-14.7) years, respectively. 34 were on tenofovir alafenamide fumarate/emtricitabine, 12 on abacavir/lamivudine and 13 on zidovudine/lamivudine backbone. 29 children were on 600/100 mg, and 30 were on 800/100 mg darunavir/ritonavir, both once-daily, based on simplified WHO weight-band based doses[6].
A two-compartment disposition model with transit absorption compartments best described the data. Allometrically scaling clearance and volume parameters by weight improved the model fit (dOFV=27.9). The typical value of clearance was 7.94 (95%CI 7.03-8.94) L/h, with 32.7 (26.3-40.1) % BSV, and volume of distribution was 46.3 (95% CI 37.3-57.5) L. A combined residual error model with 12.5 (95%CI 0.5-14.9) % proportional error and 0.309 (95%CI 0.227-0.416) mg/L additive error was sufficient for the data. The relationship between AAG and darunavir clearance was best described by an inverse linear relationship where darunavir’s binding to AAG depended on a KAFF of 0.661 (95%CI 0.299–1.04) L/mg. The model fit significantly improved (dOFV=12.7, p<0.001) and 12.8% of the between subject variability in clearance was explained. No effect of ritonavir concentrations or NRTI backbones could be found on darunavir bioavailability or clearance.
Conclusions: Darunavir total clearance is altered by AAG concentrations. There is need for further investigation of the clinical significance of this effect. We found no significant effect of ritonavir on darunavir exposure, suggesting that both 800/100 and 600/100 provide adequate ritonavir for maximum boosting, making it difficult for the model to tease out any additional effect. Lastly, the NRTIs used in this study have no significant effect on darunavir exposure.
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