{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Dooley KE"],"funding":["NCATS NIH HHS","NIAID NIH HHS","NIGMS NIH HHS"],"pagination":["3399-405"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4432148"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["59(6)"],"pubmed_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.)."],"journal":["Antimicrobial agents and chemotherapy"],"pubmed_title":["Novel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers."],"pmcid":["PMC4432148"],"funding_grant_id":["UM1 AI069423","UM1 AI106701","P30 AI050410","K23AI080842","P30 AI50410","1UL1 TR001111","UM1 AI068634","AI069423","UL1 TR001079","UM1 AI068636","UL1 TR001111","K23 AI080842","UM1 AI069439","K24 AI104830","2UM1 AI069465","UL1 TR000445","UM1AI106701","2UM1 AI069439-08","U01 AI069423","UM1 AI069465","UM1 AI069432","U01 AI068634","T32 GM066691"],"pubmed_authors":["Dorman SE","Park JG","Patterson K","Benson CA","Hovind L","Hogg E","Marzinke MA","Dooley KE","Cramer Y","ACTG A5311 Study Team","Janik J","Savic RM","Haas DW","Hafner R"],"additional_accession":[]},"is_claimable":false,"name":"Novel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers.","description":"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.).","dates":{"release":"2015-01-01T00:00:00Z","publication":"2015","modification":"2026-05-04T02:01:29.638Z","creation":"2025-05-18T11:35:11.105Z"},"accession":"S-EPMC4432148","cross_references":{"pubmed":["25824215"],"doi":["10.1128/aac.05128-14","10.1128/AAC.05128-14"]}}