A Dose-Ranging Trial to Optimize the Dose of Rifampin in the Treatment of Tuberculosis

Boeree, Martin J.; Diacon, Andreas H.; Dawson, Rodney; Narunsky, Kim; Bois, Jeannine du; Venter, Amour; Phillips, Patrick P. J.; Gillespie, Stephen H.; McHugh, Timothy D.; Höelscher, Michael; Heinrich, Norbert; Rehal, Sunita; Soolingen, Dick van; Ingen, Jakko van; Ibáñez, Carmen; Burger, David M.; Balen, Georgette Plemper van; Aarnoutse, Rob E.

doi:10.1164/rccm.201407-1264oc

Cited by 274 publications

(306 citation statements)

References 28 publications

Supporting

Mentioning

270

Contrasting

Unclassified

Order By: Relevance

“…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)(2)(3)(4)(5). A recent trial of cyclopentyl-rifampin (rifapentine) demonstrated that response to therapy is driven by drug exposure, not dose (6).…”

mentioning

confidence: 99%

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

Peloquin

Velásquez

Lecca

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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

show abstract

mentioning

confidence: 99%

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

Peloquin

Velásquez

Lecca

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…7 Higher RMP dosing is supported by animal models and early bactericidal activity data. 8,9 The reluctance to investigate higher doses of RMP is due to the fear of serious hepatotoxic adverse effects. Little is known about the potential toxicity of a higher dose of RMP, as most data are derived from non-comparative cohort studies.…”

mentioning

confidence: 99%

A randomised Phase II trial to evaluate the toxicity of high-dose rifampicin to treat pulmonary tuberculosis

Jindani

Borgulya

Patino

et al. 2016

int j tuberc lung dis

View full text Add to dashboard Cite

“…Similar to TB, doses of drugs used to treat pulmonary MAC were chosen out of necessity, which even though in use for decades, it is now clear that many of the original dose choices were suboptimal: PK/PD studies and Monte Carlo simulations have identified larger doses which are now being evaluated in clinical trials (7,(10)(11)(12)(29)(30)(31)(32). Currently, azithromycin is administered at doses of 500 to 600 mg in combination therapy, based on very limited clinical data, and in the treatment of cavitary MAC pneumonia in the largest multicenter study had a microbial response rate of only 4% (1,6).…”

Section: Discussionmentioning

confidence: 99%

Azithromycin Dose To Maximize Efficacy and Suppress Acquired Drug Resistance in Pulmonary Mycobacterium avium Disease

Deshpande

Pasipanodya

Gumbo

2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

bMycobacterium avium complex is now the leading mycobacterial cause of chronic pneumonia in the United States. Macrolides and ethambutol form the backbone of the regimen used in the treatment of pulmonary disease. However, therapy outcomes remain poor, with microbial cure rates of 4% in cavitary disease. The treatment dose of azithromycin has mostly been borrowed from that used to treat other bacterial pneumonias; there are no formal dose-response studies in pulmonary M. avium disease and the optimal dose is unclear. We utilized population pharmacokinetics and pharmacokinetics/pharmacodynamics-derived azithromycin exposures associated with optimal microbial kill or resistance suppression to perform 10,000 patient Monte Carlo simulations of dose effect studies for daily azithromycin doses of 0.5 to 10 g. The currently recommended dose of 500 mg per day achieved the target exposures in 0% of patients. Exposures associated with optimal kill and resistance suppression were achieved in 87 and 54% of patients, respectively, only by the very high dose of 8 g per day. The azithromycin susceptibility breakpoint above which patients failed therapy on the very high doses of 8 g per day was an MIC of 16 mg/ liter, suggesting a critical concentration of 32 mg/liter, which is 8-fold lower than the currently used susceptibility breakpoint of 256 mg/liter. If the standard dose of 500 mg a day were used, then the critical concentration would fall to 2 mg/liter, 128-fold lower than 256 mg/liter. The misclassification of resistant isolates as susceptible could explain the high failure rates of current doses.

show abstract

A Dose-Ranging Trial to Optimize the Dose of Rifampin in the Treatment of Tuberculosis

Cited by 274 publications

References 28 publications

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

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

A randomised Phase II trial to evaluate the toxicity of high-dose rifampicin to treat pulmonary tuberculosis

Azithromycin Dose To Maximize Efficacy and Suppress Acquired Drug Resistance in Pulmonary Mycobacterium avium Disease

Contact Info

Product

Resources

About