Rifapentine Population Pharmacokinetics and Dosing Recommendations for Latent Tuberculosis Infection.

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.

• Authors: Jennifer E Hibma, Kendra K Radtke, Susan E Dorman, Amina Jindani, Kelly E Dooley, Marc Weiner, Helen M McIlleron, Radojka M Savic
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 202 Issue 6 Pg. 866-877 (09 15 2020) ISSN: 1535-4970 [Electronic] United States
• PMID: 32412342 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Systematic Review)

Chemical References

• Antibiotics, Antitubercular
• Rifampin
• rifapentine

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antibiotics, Antitubercular (pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Latent Tuberculosis (drug therapy)
• Male
• Middle Aged
• Rifampin (analogs & derivatives, pharmacokinetics, therapeutic use)
• Young Adult