Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis

Abstract

Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to receive rifampin at 10, 15, or 20 mg/kg/day. A total of 168 had noncompartmental pharmacokinetic analyses; 67% were sampled twice, and 33% were sampled six times. The doses administered were well tolerated. The median area under the concentration-time curve from 0 to 6 h (interquartile range) was 24.9 (17.6 to 32.1), 43.1 (30.3 to 57.5), or 55.5 (35.7 to 73.2) h · g/ml. The median maximum drug concentration in serum in the experimental arms reached the target of 8 g/ml. Continued investigation of higher rifampin doses is warranted. (This study has been registered at ClinicalTrials.gov under registration no. NCT01408914.) KEYWORDS tuberculosis, rifampin, pharmacokinetics, antitubercular agents R ifampin's profound concentration-dependent killing of Mycobacterium tuberculosis is not exploited by the standard dose, and higher doses of rifampin appear to be well tolerated (1-5). A recent trial of cyclopentyl-rifampin (rifapentine) demonstrated that response to therapy is driven by drug exposure, not dose (6). Higher rifampin exposures potentially offer more cure, less selection for drug-resistant mutants, and a shorter treatment duration. HIRIF (ClinicalTrials registration no. NCT01408914) was a phase II, triple-blind, randomized, placebo-controlled, dose-ranging clinical trial comparing rifampin delivered orally at 10, 15, or 20 mg/kg daily for 8 weeks in Lima, Peru (7). Here we report the noncompartmental pharmacokinetic (PK) results.The study was reviewed and approved by the institutional review boards at all of the participating institutions and included consenting adults with newly diagnosed, previously untreated, smear-positive (Ͼ2ϩ) pulmonary tuberculosis. All randomized participants received standard doses of rifampin (10 mg/kg/day) and isoniazid (5 mg/kg/ day), pyrazinamide (25 mg/kg/day), and ethambutol (20 mg/kg/day) contained in fixed-dose combinations manufactured by MacLeods Pharmaceuticals in accordance with WHO dosing recommendations (Table 1) (8). Participants received additional placebo and/or rifampin doses, provided by Sanofi-Aventis Groupe, according to their study arms and body weight bands. The continuation phase was standard doses of isoniazid (10 mg/kg/day) and rifampin (10 mg/kg/day) thrice weekly for 18 weeks (7). All treatment was ambulatory and supervised by study staff. MICs (MIC 99.9 ) were determined by using nine concentrations (0.88 to 1.414 mg/liter) in 7H11 (9, 10). Participants were randomized to sparse (67%) or intensive (33%) sampling for PK

Towards individualised treatment of tuberculosis

“…Estimation of median AUC0-6h for rifampicin and isoniazid (35 and 17 mg•h/L, respectively) in study II was performed using noncompartmental analysis based on sparse sampling thus provided crude estimates. Nevertheless, results were in line with previous findings of TB patients receiving standard TB treatment achieving a median AUC0-6h for rifampicin of 24.9 mg•h/L (198). One of few other studies conducted in a low-endemic setting in Denmark included 32 patients on standard therapy against active TB and three patients on treatment for latent tuberculosis (136).…”

Impact of Clofazimine Dosing on Treatment Shortening of the First-Line Regimen in a Mouse Model of Tuberculosis

“…For the first-line anti-TB drugs, mouse dosing is based on achieving drug exposures that closely recapitulate those obtained with the recommended dosing in humans (29,70). Although there is some debate about whether these officially recommended doses are indeed the optimal doses, especially for rifampin (71,72), there are clinical PK and pharmacodynamic (PD) data and target PK/PD parameter values known to be associated with safe and effective treatment, supporting the recommended doses for each of the first-line drugs (1, 2). For clofazimine, an evidence base for dosing in patients with TB does not exist, and basic PK/PD parameters, including what exposure levels are required for antimicrobial activity, are unknown.…”

Both Pharmacokinetic Variability and Granuloma Heterogeneity Impact the Ability of the First-Line Antibiotics to Sterilize Tuberculosis Granulomas

“…There have been numerous efforts to shorten TB treatment regimens and clinical trials that involve replacing one or more antibiotics in the standard regimen or increasing doses of the firstline antibiotics (Gillespie et al, 2014;Jindani et al, 2014). Increasing RIF dosage to 20 mg/kg is a strategy applied in several clinical trials (Diacon et al, 2007;Boeree et al, 2017;Peloquin et al, 2017), and is rational because it could lessen the impact PK variability has on RIF given our results (Figure 7). We investigated how increasing the RIF dose impacts granuloma sterilization time while accounting for granuloma heterogeneity and PK variability.…”