Hibma, JE; Radtke, KK; Dorman, SE; Jindani, A; Dooley, KE; Weiner, M; McIlleron, HM; Savic, RM
(2020)
Rifapentine Population Pharmacokinetics and Dosing Recommendations for Latent Tuberculosis Infection.
Am J Respir Crit Care Med, 202 (6).
pp. 866-877.
ISSN 1535-4970
https://doi.org/10.1164/rccm.201912-2489OC
SGUL Authors: Jindani, Amina
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Abstract
RATIONALE: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms but clarity on the optimal dosing approach is lacking. OBJECTIVES: In this individual participant data meta-analysis of rifapentine pharmacokinetics, we characterize rifapentine population pharmacokinetics, including autoinduction, and determine optimal dosing strategies for short-course rifapentine-based regimens for latent tuberculosis infection. METHODS: Rifapentine pharmacokinetic studies were identified though a systematic review of literature. Individual plasma concentrations were pooled, and non-linear mixed effects modeling was performed. A subset of data was reserved for external validation. Simulations were performed under various dosing conditions including current weight-based methods and alternative methods driven by identified covariates. MEASUREMENTS AND MAIN RESULTS: We identified 9 clinical studies with a total of 863 participants with pharmacokinetic data (n=4301 plasma samples). Rifapentine population pharmacokinetics were described successfully with a one-compartment distribution model. Autoinduction of clearance was driven by rifapentine plasma concentration. The maximum effect was a 72% increase in clearance and was reached after 21 days. Drug bioavailability decreased by 27% with HIV infection, decreased by 28% with fasting, and increased by 49% with a high-fat meal. Body weight was not a clinically relevant predictor of clearance. Pharmacokinetic simulations showed that current weight-based dosing leads to lower exposures in low weight individuals, which can be overcome with flat dosing. In HIV-positive patients, 30% higher doses are required to match drug exposure in HIV-negative patients. CONCLUSIONS: Weight-based dosing of rifapentine should be removed from clinical guidelines and higher doses for HIV-positive patients should be considered to provide equivalent efficacy.
Item Type: |
Article
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Additional Information: |
Originally Published in: Jennifer E Hibma , Kendra K Radtke , Susan E Dorman , Amina Jindani , Kelly E Dooley , Marc Weiner , Helen M. McIlleron , and Radojka M. Savic . Rifapentine Population Pharmacokinetics and Dosing Recommendations for Latent Tuberculosis Infection. American Journal of Respiratory and Critical Care Medicine. 2020;202:866-877.
DOI: 10.1164/rccm.201912-2489OC
Copyright © 2020 by the American Thoracic Society
The final publication is available at https://doi.org/10.1164/rccm.201912-2489OC. |
Keywords: |
latent tuberculosis, population pharmacokinetics, rifamycins, rifapentine, tuberculosis, 11 Medical and Health Sciences, Respiratory System |
SGUL Research Institute / Research Centre: |
Academic Structure > Infection and Immunity Research Institute (INII) |
Journal or Publication Title: |
Am J Respir Crit Care Med |
ISSN: |
1535-4970 |
Language: |
eng |
Dates: |
Date | Event |
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15 September 2020 | Published | 15 May 2020 | Published Online | 14 May 2020 | Accepted |
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Publisher License: |
Publisher's own licence |
PubMed ID: |
32412342 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/111954 |
Publisher's version: |
https://doi.org/10.1164/rccm.201912-2489OC |
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