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Clinical Trial
, 102 (2), 321-331

Defining the Optimal Dose of Rifapentine for Pulmonary Tuberculosis: Exposure-response Relations From Two Phase II Clinical Trials

Affiliations
Clinical Trial

Defining the Optimal Dose of Rifapentine for Pulmonary Tuberculosis: Exposure-response Relations From Two Phase II Clinical Trials

R M Savic et al. Clin Pharmacol Ther.

Abstract

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses.

Figures

Figure 1
Figure 1
Relation between rifapentine area under the concentration–time curve from 0 to 24 h (AUC0‐24) and maximum concentration (Cmax) vs. estimated time required for 95% patients with no or small lung cavities (a) or large lung cavities (b) to achieve stable conversion to negative sputum culture. Rifapentine AUC0‐24 (gray) or Cmax (red) shown for liquid (continuous line) and solid (broken line) culture media. Estimated time to stable culture conversion for all control participants treated with rifampin during intensive‐phase therapy was 114 days in liquid media (top arrow) and 91 days on solid media (bottom arrow). Data for participants with large cavities on solid media were estimated for grade 4 acid‐fast bacilli smear from baseline sputum.
Figure 2
Figure 2
Forest plot of the relative effects of demographics, clinical covariates, and rifapentine area under the concentration–time curve from 0 to 24 h (AUC0‐24) on outcome of time (d) to culture conversion of sputum in liquid media culture. Median and 95% confidence interval are indicated by the square box and bars. Covariate effects are shown in patients taking rifampin‐based intensive‐phase therapy in the control group. Low (high) rifapentine (RPT) AUC, target rifapentine AUC0‐24 <300 (>350) μg × h/mL (AUC0‐24 from daily drug administration 7 days per week); low (high) radiographic extent of disease, <50% (≥50%) lung area by baseline chest radiograph; productive cough, productive cough at entry into the phase IIB treatment trials; large lung cavity (small or no lung cavity) on radiograph, aggregate size ≥4 cm (<4 cm); RHZE, Control regimen during intensive‐phase therapy of rifampin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E); RPT, rifapentine.
Figure 3
Figure 3
Relation between rifapentine area under the concentration–time curve (AUC) from 0 to 24 h (AUC0‐24) vs. dose (900 or 1,200 mg) and food type (high fat (hf), >27 g fat; lower fat (lf), 1 to 27 g fat; or fasting (fast)). Target rifapentine AUC0‐24 needed for 95% participants with no or small (<4 cm) lung cavities at baseline radiograph to achieve persistently negative cultures (AUC95) in liquid media indicated by the green horizontal line. Insufficient exposure indicated by the red line. Model estimates of rifapentine AUC95 and Figure 1 were used to formulate target cutoffs of rifapentine AUC0‐24 >350 μg × h/mL and low target rifapentine AUC0‐24 of <300 μg × h/mL using sputa cultures in liquid media.

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