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  • PA-727 Physiologically-based pharmacokinetic modelling of drug-drug interactions between ritonavir-boosted atazanavir and rifampicin in pregnancy

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PA-727 Physiologically-based pharmacokinetic modelling of drug-drug interactions between ritonavir-boosted atazanavir and rifampicin in pregnancy
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  1. Shakir Atoyebi1,
  2. Maiara Camotti Montanha1,
  3. Letisha Najjemba2,
  4. Catherine Orrell3,
  5. Lauren Jennings3,
  6. Henry Mugerwa4,
  7. Aida Kawuma2,
  8. Francis Ojara2,
  9. Marco Siccardi1,
  10. Paolo Denti5,
  11. Catriona Waitt1,2
  1. 1University of Liverpool, UK
  2. 2Infectious Diseases Institute, Makerere University College of Health Sciences, Uganda
  3. 3Desmond Tutu Health Foundation, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, South Africa
  4. 4Joint Clinical Research Centre, Uganda
  5. 5Division of Pharmacology, Department of Medicine, University of Cape Town, South Africa

Abstract

Background Ritonavir-boosted atazanavir (ATV/r) and rifampicin are mainstays of second-line antiretroviral and multiple anti-TB regimens, respectively. Rifampicin is a strong inducer of CYP3A4, the main enzyme involved in atazanavir metabolism, causing drug-drug interaction (DDI) in those co-infected with HIV and TB, which might be exaggerated in pregnancy. We employed physiologically-based pharmacokinetic (PBPK) modelling to investigate atazanavir pharmacokinetics during coadministration of rifampicin and ATV/r in pregnancy.

Methods A pregnancy PBPK model was developed from a published adult PBPK model by incorporating pregnancy-induced biological changes. Predicted pharmacokinetic parameters in pregnancy were validated with published clinical datasets for once daily (OD) rifampicin 600 mg and clinical data for ATV/r (300/100 mg) in pregnancy (NCT03923231). Predicted atazanavir Ctrough was compared against its protein-adjusted IC90 (14 ng/ml) when simulating the coadministration of ATV/r 300/100 mg OD and rifampicin 600 mg OD in pregnancy. Alternative dosing regimens were also explored.

Results The pregnancy model was considered validated when the absolute average fold error (AAFE) for Ctrough and AUC0–24 of ATV/r 300/100 mg OD and for Cmax and AUC0–24 for rifampicin 600 mg OD were <2, when comparing predicted vs observed data. Similarly, comparison of predicted and observed plasma concentrations of atazanavir and ritonavir in the sparse pregnancy data (NCT03923231) gave AAFE values <2. Pregnancy was predicted to increase the rifampicin DDI effect on atazanavir. For the dosing regimens of ATV/r 300/100 mg OD, ATV/r 300/200 mg OD and ATV/r 300/100 mg BD (all with rifampicin 600 mg OD), predicted atazanavir Ctrough was above 14 ng/ml in 29%, 71% and 100%; and 32%, 73% and 100% of the population in second and third trimesters, respectively.

Conclusion PBPK modelling suggests ATV/r 300/100 mg BD could maintain antiviral efficacy when co-administered with rifampicin 600 mg OD in pregnancy. Clinical studies are warranted to confirm safety and efficacy in pregnancy.

https://doi.org/10.1136/bmjgh-2023-EDC.279

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