Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin

Allan Kengo; Kamunkhwala Gausi; Ruth Nabisere; Joseph Musaazi; Allan Buzibye; Denis Omali; Rob Aarnoutse; Mohammed Lamorde; Kelly E. Dooley; Derek James Sloan; Christine Sekaggya-Wiltshire; Paolo Denti

doi:10.1128/aac.00431-23

Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin

Allan Kengo, Kamunkhwala Gausi, Ruth Nabisere, Joseph Musaazi, Allan Buzibye, Denis Omali, Rob Aarnoutse, Mohammed Lamorde, Kelly E. Dooley, Derek James Sloan, Christine Sekaggya-Wiltshire, Paolo Denti^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.

Original language	English
Article number	e00431-23
Number of pages	6
Journal	Antimicrobial Agents and Chemotherapy
Volume	67
Issue number	11
Early online date	18 Oct 2023
DOIs	https://doi.org/10.1128/aac.00431-23
Publication status	Published - 15 Nov 2023

Keywords

Rifampicin
High-dose
Pharmacokinetics
Bioavailability
Top-up capsule

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1128/aac.00431-23

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10649026/

Cite this

Kengo, A., Gausi, K., Nabisere, R., Musaazi, J., Buzibye, A., Omali, D., Aarnoutse, R., Lamorde, M., Dooley, K. E., Sloan, D. J., Sekaggya-Wiltshire, C., & Denti, P. (2023). Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin. Antimicrobial Agents and Chemotherapy, 67(11), Article e00431-23. https://doi.org/10.1128/aac.00431-23

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title = "Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin",

abstract = "We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.",

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author = "Allan Kengo and Kamunkhwala Gausi and Ruth Nabisere and Joseph Musaazi and Allan Buzibye and Denis Omali and Rob Aarnoutse and Mohammed Lamorde and Dooley, {Kelly E.} and Sloan, {Derek James} and Christine Sekaggya-Wiltshire and Paolo Denti",

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AU - Kengo, Allan

AU - Gausi, Kamunkhwala

AU - Nabisere, Ruth

AU - Musaazi, Joseph

AU - Buzibye, Allan

AU - Omali, Denis

AU - Aarnoutse, Rob

AU - Lamorde, Mohammed

AU - Dooley, Kelly E.

AU - Sloan, Derek James

AU - Sekaggya-Wiltshire, Christine

AU - Denti, Paolo

N1 - EC | H2020 | ERA-LEARN | European and Developing Countries Clinical Trials Partnership (EDCTP) TMA2016CDF-1580, EC | H2020 | ERA-LEARN | European and Developing Countries Clinical Trials Partnership (EDCTP) RIA2016MC-1606-Vir TUAL, HHS | NIH | NIH Office of the Director (OD) K24AI150349, Scottish Funding Council (SFC). Additional support was provided by a Global Challenges Research Fund award from the Scottish Funding Council, administered via the University of St. Andrews.

PY - 2023/11/15

Y1 - 2023/11/15

N2 - We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.

AB - We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.

KW - Rifampicin

KW - High-dose

KW - Pharmacokinetics

KW - Bioavailability

KW - Top-up capsule

UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10649026/

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VL - 67

JO - Antimicrobial Agents and Chemotherapy

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IS - 11

M1 - e00431-23

ER -

Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin

Abstract

Keywords

UN SDGs

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