Physiologically based pharmacokinetic modelling of the co-administration of ritonavir-boosted atazanavir and rifampicin in children co-treated for HIV and TB

Abstract

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Physiologically based pharmacokinetic modelling of the co-administration of ritonavir-boosted atazanavir and rifampicin in children co-treated for HIV and TB

Shakir Atoyebi¹, Maiara Montanha¹, Catherine Orrell², Henry Mugerwa³, Marco Siccardi^1,4, Paolo Denti⁵ and Catriona Waitt^1,6

¹Department of Pharmacology & Therapeutics, University of Liverpool; ²Desmond Tutu Health Foundation, Institute of Infectious Disease and Molecular Medicine & Department of Medicine, University of Cape Town; ³Joint Clinical Research Centre; ⁴ESQlabs GmbH; ⁵Division of Pharmacology, Department of Medicine, University of Cape Town; ⁶Infectious Diseases Institute, Makerere University College of Health Sciences

Background: Children living with HIV are disproportionately affected by tuberculosis. Limited options are available for adequate treatment of both diseases because rifampicin, a mainstay of several anti-TB regimens, reduces the exposure of multiple antiretrovirals like ritonavir-boosted atazanavir (ATV/r). Recent modelling and clinical studies (DERIVE [NCT04121195]) suggest doubling the dose of ATV/r 300/100 mg from once to twice daily would overcome the drug–drug interaction (DDI) effect with rifampicin in adults. In this study, physiologically based pharmacokinetic (PBPK) modelling was used to investigate if twice daily dosing of ATV/r could overcome the DDI effect of standard doses of rifampicin in children.

Material and methods: The published PBPK model used for studying DDI between ATV/r and rifampicin in adults was modified into its paediatric version. Equations describing key anatomical and physiological parameters (e.g. organ weights and blood flow) were modified to paediatric versions between ages 7 and 18 years. Adult levels of enzyme activity were maintained in the paediatric model. Rifampicin's drug absorption rate, apparent clearance and volume of distribution were also modified to paediatric values within the simple compartment used to model rifampicin PK. Model predictions were validated using observed clinical PK data of ATV/r alone and rifampicin alone in children with acceptability criteria maintained as absolute average fold error less than 2 between simulated and observed values. ATV/r 300/100 mg once daily and twice daily were each simulated with co-administered 300, 450 and 600 mg rifampicin in children distributed in three weight bands: 25–30 kg (7–11 years), 30–39 kg (8–14 years) and 50–70 kg (12–18 years), respectively. Simulated ATV Ctrough was compared against a clinical cut-off, ATV protein binding-adjusted 90% inhibitory concentration (PAIC90, 14 ng/mL).

Results: The paediatric PBPK model was adequately validated with simulated PK of atazanavir and rifampicin having AAFEs <2 compared to their corresponding observed values. With ATV/r 300/100 mg once daily, standard doses of rifampicin reduced ATV C_trough and AUC by 99% and 67%, 99% and 72% and 99.8% and 78% in children weighing 25–35 kg, 30–49 kg and 50–70 kg, respectively. In the same weight-bands, 42%, 65% and 94% of the simulated population were predicted to have ATV Ctrough <PAIC90, respectively. When increasing ATV/r to 300/100 mg twice daily with standard doses of rifampicin, 9%, 4% and 9% of the simulated population of children were predicted to have ATV C_trough less than the PAIC90, respectively.

Conclusion: Modelling suggests that co-administration of once daily standard doses of rifampicin with ATV/r 300/100 mg given twice daily would maintain efficacious ATV concentrations in children weighing 25–70 kg (7–18 years). Clinical studies in children are needed to confirm the safety and efficacy of these dosing combinations in children.