Novel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers.

TitleNovel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers.
Publication TypeJournal Article
Year of Publication2015
AuthorsDooley KE, Savic RM, Park J-G, Cramer Y, Hafner R, Hogg E, Janik J, Marzinke MA, Patterson K, Benson CA, Hovind L, Dorman SE, Haas DW
Corporate AuthorsACTG A5311 Study Team
JournalAntimicrob Agents Chemother
Volume59
Issue6
Pagination3399-405
Date Published2015
ISSN1098-6596
KeywordsAdolescent, Adult, Aged, Antitubercular Agents, Drug Administration Schedule, Female, Healthy Volunteers, Humans, Male, Middle Aged, Rifampin, Young Adult
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.).

DOI10.1128/AAC.05128-14
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID25824215
PubMed Central IDPMC4432148
Grant List1UL1 TR001111 / TR / NCATS NIH HHS / United States
2UM1 AI069439-08 / AI / NIAID NIH HHS / United States
2UM1 AI069465 / AI / NIAID NIH HHS / United States
AI069423 / AI / NIAID NIH HHS / United States
K23AI080842 / AI / NIAID NIH HHS / United States
K24 AI104830 / AI / NIAID NIH HHS / United States
P30 AI050410 / AI / NIAID NIH HHS / United States
P30 AI50410 / AI / NIAID NIH HHS / United States
U01 AI068634 / AI / NIAID NIH HHS / United States
UL1 TR000445 / TR / NCATS NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI069423 / AI / NIAID NIH HHS / United States
UM1 AI069432 / AI / NIAID NIH HHS / United States
UM1 AI069439 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States
UM1AI106701 / AI / NIAID NIH HHS / United States