Population Pharmacokinetic Modeling and Simulation of Rifapentine Supports Concomitant Antiretroviral Therapy with Efavirenz and Non-Weight Based Dosing

Abstract

The Brief Rifapentine-Isoniazid Efficacy for TB Prevention/A5279 trial demonstrated a 1-month daily regimen of rifapentine and isoniazid was noninferior to 9 months of isoniazid alone for preventing TB in persons living with HIV (PLWH). Our objective was to evaluate rifapentine pharmacokinetics in trial participants receiving antiretroviral therapy (ART) and perform simulations to compare weight-based rifapentine dosing with a standard, fixed dose. Nonlinear mixed effect modeling was used to estimate rifapentine and 25-desacetyl rifapentine population pharmacokinetic characteristics. The pharmacokinetic model was validated using a nonparametric bootstrap and visual predictive checks. Monte Carlo simulations were performed to compare weight-based and fixed dose regimens. Rifapentine and 25-desacetyl rifapentine concentrations (347 of each; 185 participants) were each described with a one-compartment model with one-way conversion between rifapentine and 25-desacetyl rifapentine. The absorption rate was nearly doubled in fed versus fasting states. Rifapentine clearance was increased 31% in those receiving efavirenz (EFV)-based versus nevirapine-based ART. Metabolite clearance was allometrically scaled with fat-free mass. Simulations showed lower rifapentine exposures with weight-based compared with fixed dosing. With 10 mg/kg weight-based regimens, 26% and 62% of simulated exposures in <35 kg and 35-45 kg weight classes were above target (AUC0 to 24 h of 257 mg*hr/L); 85% of simulated exposures across all weight classes with fixed dosing were above target. These data support fixed dosing with rifapentine 600 mg daily for TB prevention regardless of weight for PLWH 13 years or older receiving the 4-week regimen and no need for dose adjustment when given with EFV-based ART. Clinical Trials Registration. NCT01404312.

Keywords: HIV/AIDS; Mycobacterium tuberculosis; antiretroviral therapy; population pharmacokinetics; rifapentine; tuberculosis.

Conflict of interest statement

The authors declare a conflict of interest. Susan Swindells reports research grants from ViiV Healthcare. Constance A. Benson reports research grants to her institution from Gilead Sciences.

Figures

FIG 1

Rifapentine and 25-desacetyl rifapentine concentrations. A. Rifapentine concentrations post dose. B. 25-desacetyl rifapentine concentrations post rifapentine dose.

FIG 2

Simulated rifapentine concentrations comparing flat and weight-based dosing scenarios across time post dose. The line within the box refers to the median. The box is the interquartile range (lower: first quantile, upper: third quantile). The upper whisker extends to the largest value extending no further than 1.5 times the interquartile range. The lower whisker extends to the smallest value extending no further than 1.5 the interquartile range. Any points, data past the whiskers, are outliers.

FIG 3

Simulated AUCs comparing dosing scenarios by weight class. The dashed line represents the target AUC: 257 mg*h/L. The line within the box refers to the median. The box is the interquartile range (lower: first quantile, upper: third quantile). The upper whisker extends to the largest value extending no further than 1.5 times the interquartile range. The lower whisker extends to the smallest value extending no further than 1.5 the interquartile range. Any points, data past the whiskers, are outliers.