AAC Accepts, published online ahead of print on 2 September 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00554-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Repeated Administration of High-Dose Intermittent Rifapentine Reduces Rifapentine and Moxifloxacin Plasma Concentrations

Kelly Dooley, Charles Flexner, Judith Hackman, Charles A. Peloquin, Eric Nuermberger, Richard E. Chaisson, and Susan E. Dorman^*

Divisions of Infectious Diseases, and Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD; Infectious Disease Pharmacokinetics Laboratory, National Jewish Medical and Research Center, Denver, CO

^* To whom correspondence should be addressed. Email: dsusan1{at}jhmi.edu.

Background: Moxifloxacin- and rifapentine-based regimens are under investigation for treatment of tuberculosis. However, rifapentine may induce enzymes that metabolize moxifloxacin, resulting in decreased moxifloxacin concentrations.

Methods: In this Phase I, two-period, sequential-design study, 13 subjects received moxifloxacin 400 mg daily for 4 days followed by daily moxifloxacin co-administered with rifapentine 900 mg thrice-weekly. Pharmacokinetic analyses were performed after the 4^th and 19^th doses of moxifloxacin and after the 1^st and 7^th doses of rifapentine.

Results: For moxifloxacin, mean area under the concentration-time curve from 0 to 24 hours (AUC_0-24) decreased by 17.2% (p=0.0006) when co-administered with rifapentine, and mean half-life (t_1/2) decreased from 11.1 to 8.9 hours (p=0.0033). For rifapentine, mean AUC_0-48 after 7 thrice-weekly doses decreased by 20.3% (p=0.0035) compared to the AUC_0-48 after the first dose, and mean t_1/2 decreased from 18.5 to 14.8 hours (p=0.0004). AUC_0-48 for the 25-desacetyl-rifapentine metabolite diminished 21%. Two days after completing study drugs, one subject developed fever and hepatitis and another developed a flu-like illness with rash.

Conclusions: Rifapentine modestly reduced moxifloxacin concentrations. Changes consistent with rifapentine autoinduction of metabolism were seen. Adverse reactions in two subjects may have represented rifamycin hypersensitivity syndromes, although some features were atypical.

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