Abstract
Rationale: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms, but clarity on the optimal dosing approach is lacking. Objectives: To 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 nonlinear 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 nine clinical studies with a total of 863 participants with pharmacokinetic data (n = 4,301 plasma samples). Rifapentine population pharmacokinetics were described successfully with a one-compartment distribution model. Autoinduction of clearance was driven by rifapentine plasma concentrations. 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 individuals with low weight, 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.
Original language | English (US) |
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Pages (from-to) | 866-877 |
Number of pages | 12 |
Journal | American journal of respiratory and critical care medicine |
Volume | 202 |
Issue number | 6 |
DOIs | |
State | Published - Sep 15 2020 |
Keywords
- Latent tuberculosis
- Population pharmacokinetics
- Rifamycins
- Rifapentine
- Tuberculosis
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine