Rifapentine Population Pharmacokinetics and Dosing Recommendations for Latent Tuberculosis Infection.
Am J Respir Crit Care Med
; 202(6): 866-877, 2020 09 15.
Article
em En
| MEDLINE
| ID: mdl-32412342
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 MainResults:
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Rifampina
/
Relação Dose-Resposta a Droga
/
Tuberculose Latente
/
Antibióticos Antituberculose
Tipo de estudo:
Systematic_reviews
Limite:
Adolescent
/
Adult
/
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article