Jennie van Dyk1, Catriona Waitt2,3, Henry Mugerwa4, Lubbe Wiesner1, Catherine Orrell5, Alasdair Bamford6,7, Diana M Gibb6, Helen M McIlleron1,8, Angela Colbers9, David M Burger9, Paolo Denti1, Roeland E Wasmann1, CHAPAS-4 and VirTUAL trial team
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , 2Infectious Diseases Institute, Makerere University College of Health Sciences, 3Department of Women’s and Children’s Health, University of Liverpool, 4Joint Clinical Research Centre, 5Desmond Tutu HIV Centre, University of Cape Town, 6Medical Research Council Clinical Trials Unit, University College London, 7Infection, Immunity & Inflammation Department, UCL Great Ormond Street Hospital Institute of Child Health, 8Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 9Department of Pharmacy, Radboud University Medical Center
Introduction / objectives: Boosted protease inhibitors (bPIs) are key components of second-line therapy for children and adults living with HIV who experience treatment failure on first-line regimens. Ritonavir-boosted atazanavir (atazanavir/ritonavir) has advantages over some other bPIs due to lower toxicity and once daily dosing. It is dosed at 300/100 mg as a fixed-dose combination (FDC) tablet in adults and adolescents, but its use in children younger than six years is limited by a lack of paediatric formulations, which requires further investigation [1]. This study aims to develop a population pharmacokinetic model of ritonavir-boosted atazanavir in children and adolescents. Methods: Data in children with HIV receiving atazanavir/ritonavir were obtained from the CHAPAS-4 (ISRCTN22964075) and VirTUAL (NCT03923231) trials. CHAPAS-4 was a 4×2 open-label factorial randomised trial assessing second-line antiretrovirals and formulations in children aged 3 to 15 years with first-line antiretroviral therapy failure. Participants received one of four second-line anchor drugs alongside a tenofovir alafenamide-based or standard-of-care backbone. Those assigned to atazanavir/ritonavir received either 300/100 mg as an FDC tablet if =25 kg or 2×100 mg atazanavir tablets with 3×25 mg or 100 mg ritonavir tablet if 15-<25 kg, administered once daily. After 6 weeks of initiating second-line treatment, participants underwent intensive sampling over 24 hours prior to and following administration of atazanavir/ritonavir with food. VirTUAL was a separate observational study in children and adolescents receiving atazanavir/ritonavir as part of clinical care. Sparse sampling (with time points prior to and up to 6 hours post dose, or once on arrival and again after completion of routine clinic procedures) was conducted across three clinic visits. Atazanavir was quantified using LC-MS/MS with a lower limit of quantification (LLOQ) of 0.105 mg/L and 0.030 mg/L in CHAPAS-4 and VirTUAL, respectively. Concentration-time data were analysed using nonlinear mixed effects modelling in NONMEM (v.7.5.1) with FOCE-I parameter estimation and statistical and graphical analysis in R (v.4.3.1). Allometry using weight or fat-free mass [2] was applied to clearance and volume parameters. The effects of ritonavir dose and atazanavir formulation was tested on model parameters. Data below the LLOQ were imputed to 0 (M7+ method) with extra additive error component of 100% LLOQ for the imputed data, as described before [3]. Model fit was assessed with individual plots, goodness-of-fit diagnostics and visual predictive check (VPC). External validation was conducted by assessing the predictive performance of the model with data from the VirTUAL trial using a VPC. Results: The CHAPAS-4 trial provided data in 59 children receiving atazanavir/ritonavir (300/100 mg, n = 31; 200/100 mg, n = 4; 200/75 mg, n = 24), with a total of 488 observations, and a median (range) age 9.8 (3.2-15.6) years, weight 27 (15-64) kg, and fat-free mass 21 (12-44) kg. External validation was conducted using data from the VirTUAL trial in 9 children with median (range) age 15.8 (12.5–17.7) years, weight 47 (34–85) kg, and fat-free mass of 39 (27-49) kg), with a total of 30 observations. These children were receiving either 300 (n = 7), 200 (n = 1), or 150 (n = 1) mg of atazanavir with 100 mg of ritonavir. A two-compartment model with lag and sequential zero- and first-order absorption with first-order elimination best described atazanavir disposition. Clearance and volume were allometrically scaled using fat-free mass scaled to 21 kg fat-free mass. The estimated typical (95%CI) clearance of atazanavir was 4.58 (4.00-5.00) L/h with a between subject variability of 20.9% (15.3-22.3%). In CHAPAS-4 trial participants receiving 2×100 mg atazanavir tablets, atazanavir bioavailability was 25.7% (16.2-35.6%) lower than in participants receiving the 300/100 mg FDC tablet. A VPC indicated the developed model could accurately describe external data from VirTUAL. Conclusion: The population pharmacokinetic model developed using CHAPAS-4 trial data adequately characterized atazanavir pharmacokinetics in children and adolescents and was externally validated with data from the VirTUAL trial. Children 15-<25 kg receiving 2×100 mg atazanavir tablets with 75 mg ritonavir had comparable bioavailability to that previously reported in paediatric populations [4], whereas higher bioavailability was observed in children =25 kg receiving a 300/100 mg atazanavir/ritonavir tablet.
[1] World Health Organization, Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring : recommendations for a public health approach. Geneva: World Health Organization, 2021. [2] H. S. Al-Sallami, A. Goulding, A. Grant, R. Taylor, N. Holford, and S. B. Duffull, “Prediction of Fat-Free Mass in Children,” Clin Pharmacokinet, vol. 54, no. 11, pp. 1169–1178, Nov. 2015, doi: 10.1007/s40262-015-0277-z. [3] Marie Wijk, Roeland Wasmann, Karen Jacobson, Elin Svensson, and Paolo Denti, “ A pragmatic approach to handling data below the lower limit of quantification in complex pharmacokinetic models,” in Population Approach Group Europe , 2024. [4] F. Foissac et al., “Population pharmacokinetics of atazanavir/ritonavir in HIV-1-infected children and adolescents,” Br J Clin Pharmacol, vol. 72, no. 6, pp. 940–947, Dec. 2011, doi: 10.1111/j.1365-2125.2011.04035.x.
Reference: PAGE 33 (2025) Abstr 11722 [www.page-meeting.org/?abstract=11722]
Poster: Drug/Disease Modelling - Paediatrics