Physiologically based pharmacokinetic modeling of drug–drug interactions between ritonavir‐boosted atazanavir and rifampicin in pregnancy
Abstract Ritonavir‐boosted atazanavir (ATV/r) and rifampicin are mainstays of second‐line antiretroviral and multiple anti‐TB regimens, respectively. Rifampicin induces CYP3A4, a major enzyme involved in atazanavir metabolism, causing a drug–drug interaction (DDI) which might be exaggerated in pregn...
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| Format: | Article |
| Language: | English |
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Wiley
2024-11-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13268 |
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| author | Shakir Atoyebi Maiara Camotti Montanha Ritah Nakijoba Catherine Orrell Henry Mugerwa Marco Siccardi Paolo Denti Catriona Waitt |
| author_facet | Shakir Atoyebi Maiara Camotti Montanha Ritah Nakijoba Catherine Orrell Henry Mugerwa Marco Siccardi Paolo Denti Catriona Waitt |
| author_sort | Shakir Atoyebi |
| collection | DOAJ |
| description | Abstract Ritonavir‐boosted atazanavir (ATV/r) and rifampicin are mainstays of second‐line antiretroviral and multiple anti‐TB regimens, respectively. Rifampicin induces CYP3A4, a major enzyme involved in atazanavir metabolism, causing a drug–drug interaction (DDI) which might be exaggerated in pregnancy. Having demonstrated that increasing the dose of ATV/r from once daily (OD) to twice daily (BD) in non‐pregnant adults can safely overcome this DDI, we developed a pregnancy physiologically based pharmacokinetic (PBPK) model to explore the impact of pregnancy. Predicted pharmacokinetic parameters were validated with separate clinical datasets of ATV/r alone (NCT03923231) and rifampicin alone in pregnant women. The pregnancy model was considered validated when the absolute average fold error (AAFE) for Ctrough and AUC0‐24 of both drugs were <2 when comparing predicted vs. observed data. Thereafter, predicted atazanavir Ctrough was compared against its protein‐adjusted IC90 (14 ng/mL) when simulating the co‐administration of ATV/r 300/100 mg OD and rifampicin 600 mg OD. 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. Thus, PBPK modeling 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. |
| format | Article |
| id | doaj-art-bf624ba053114f7ba65257c70d17ada7 |
| institution | Kabale University |
| issn | 2163-8306 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
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| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj-art-bf624ba053114f7ba65257c70d17ada72024-11-20T17:18:44ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062024-11-0113111967197710.1002/psp4.13268Physiologically based pharmacokinetic modeling of drug–drug interactions between ritonavir‐boosted atazanavir and rifampicin in pregnancyShakir Atoyebi0Maiara Camotti Montanha1Ritah Nakijoba2Catherine Orrell3Henry Mugerwa4Marco Siccardi5Paolo Denti6Catriona Waitt7Department of Pharmacology and Therapeutics University of Liverpool Liverpool UKDepartment of Pharmacology and Therapeutics University of Liverpool Liverpool UKInfectious Diseases Institute Makerere University College of Health Sciences Kampala UgandaDesmond Tutu Health Foundation, Institute of Infectious Disease and Molecular Medicine University of Cape Town Cape Town South AfricaJoint Clinical Research Centre Kampala UgandaDepartment of Pharmacology and Therapeutics University of Liverpool Liverpool UKDivision of Pharmacology, Department of Medicine University of Cape Town Cape Town South AfricaDepartment of Pharmacology and Therapeutics University of Liverpool Liverpool UKAbstract Ritonavir‐boosted atazanavir (ATV/r) and rifampicin are mainstays of second‐line antiretroviral and multiple anti‐TB regimens, respectively. Rifampicin induces CYP3A4, a major enzyme involved in atazanavir metabolism, causing a drug–drug interaction (DDI) which might be exaggerated in pregnancy. Having demonstrated that increasing the dose of ATV/r from once daily (OD) to twice daily (BD) in non‐pregnant adults can safely overcome this DDI, we developed a pregnancy physiologically based pharmacokinetic (PBPK) model to explore the impact of pregnancy. Predicted pharmacokinetic parameters were validated with separate clinical datasets of ATV/r alone (NCT03923231) and rifampicin alone in pregnant women. The pregnancy model was considered validated when the absolute average fold error (AAFE) for Ctrough and AUC0‐24 of both drugs were <2 when comparing predicted vs. observed data. Thereafter, predicted atazanavir Ctrough was compared against its protein‐adjusted IC90 (14 ng/mL) when simulating the co‐administration of ATV/r 300/100 mg OD and rifampicin 600 mg OD. 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. Thus, PBPK modeling 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/10.1002/psp4.13268 |
| spellingShingle | Shakir Atoyebi Maiara Camotti Montanha Ritah Nakijoba Catherine Orrell Henry Mugerwa Marco Siccardi Paolo Denti Catriona Waitt Physiologically based pharmacokinetic modeling of drug–drug interactions between ritonavir‐boosted atazanavir and rifampicin in pregnancy CPT: Pharmacometrics & Systems Pharmacology |
| title | Physiologically based pharmacokinetic modeling of drug–drug interactions between ritonavir‐boosted atazanavir and rifampicin in pregnancy |
| title_full | Physiologically based pharmacokinetic modeling of drug–drug interactions between ritonavir‐boosted atazanavir and rifampicin in pregnancy |
| title_fullStr | Physiologically based pharmacokinetic modeling of drug–drug interactions between ritonavir‐boosted atazanavir and rifampicin in pregnancy |
| title_full_unstemmed | Physiologically based pharmacokinetic modeling of drug–drug interactions between ritonavir‐boosted atazanavir and rifampicin in pregnancy |
| title_short | Physiologically based pharmacokinetic modeling of drug–drug interactions between ritonavir‐boosted atazanavir and rifampicin in pregnancy |
| title_sort | physiologically based pharmacokinetic modeling of drug drug interactions between ritonavir boosted atazanavir and rifampicin in pregnancy |
| url | https://doi.org/10.1002/psp4.13268 |
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