title: Novel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers.
abstract: Rifapentine is a potent antituberculosis drug currently in phase III trials. Bioavailability decreases with increasing dose, yet high daily exposures are likely needed to improve efficacy and shorten the tuberculosis treatment duration. Further, the limits of tolerability are poorly defined. The phase I multicenter trial in healthy adults described here investigated two strategies to increase rifapentine exposures: dividing the dose or giving the drug with a high-fat meal. In arm 1, rifapentine was administered at 10 mg/kg of body weight twice daily and 20 mg/kg once daily, each for 14 days, separated by a 28-day washout; the dosing sequence was randomized. In arm 2, 15 mg/kg rifapentine once daily was given with a high-fat versus a low-fat breakfast. Sampling for pharmacokinetic analysis was performed on days 1 and 14. Population pharmacokinetic analyses were performed. This trial was stopped early for poor tolerability and because of safety concerns. Of 44 subjects, 20 discontinued prematurely; 11 of these discontinued for protocol-defined toxicity (a grade 3 or higher adverse event or grade 2 or higher rifamycin hypersensitivity). Taking rifapentine with a high-fat meal increased the median steady-state area under the concentration-time curve from time zero to 24 h (AUC0-24ss) by 31% (relative standard error, 6%) compared to that obtained when the drug was taken with a low-fat breakfast. Dividing the dose increased exposures substantially (e.g., 38% with 1,500 mg/day). AUC0-24ss was uniformly higher in our study than in recent tuberculosis treatment trials, in which toxicity was rare. In conclusion, two strategies to increase rifapentine exposures, dividing the dose or giving it with a high-fat breakfast, successfully increased exposures, but toxicity was common in healthy adults. The limits of tolerability in patients with tuberculosis remain to be defined. (AIDS Clinical Trials Group study A5311 has been registered at ClinicalTrials.gov under registration no. NCT01574638.).
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA kdooley1@jhmi.edu.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.affiliation: University of California, San Francisco, California, USA.
authors.forename: Radojka M
authors.initials: RM
authors.lastname: Savic
authors.affiliation: Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Jeong-Gun
authors.initials: JG
authors.lastname: Park
authors.affiliation: Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Yoninah
authors.initials: Y
authors.lastname: Cramer
authors.affiliation: Division of AIDS, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hafner
authors.affiliation: Social & Scientific Systems, Inc., Silver Spring, Maryland, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hogg
authors.affiliation: Frontier Science Foundation, Amherst, New York, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Janik
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Marzinke
authors.affiliation: University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Patterson
authors.affiliation: University of California, San Diego, California, USA.
authors.forename: Constance A
authors.initials: CA
authors.lastname: Benson
authors.affiliation: Frontier Science Foundation, Amherst, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Hovind
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Dorman
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D012293:Rifampin; C018421:rifapentine
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