title: Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers.
abstract: Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AU C0–24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. kdooley1@jhmi.edu
authors.forename: K E
authors.initials: KE
authors.lastname: Dooley
authors.forename: E E
authors.initials: EE
authors.lastname: Bliven-Sizemore
authors.forename: M
authors.initials: M
authors.lastname: Weiner
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: E L
authors.initials: EL
authors.lastname: Nuermberger
authors.forename: W C
authors.initials: WC
authors.lastname: Hubbard
authors.forename: E J
authors.initials: EJ
authors.lastname: Fuchs
authors.forename: M T
authors.initials: MT
authors.lastname: Melia
authors.forename: W J
authors.initials: WJ
authors.lastname: Burman
authors.forename: S E
authors.initials: SE
authors.lastname: Dorman
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000995:Antitubercular Agents; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D012293:Rifampin; C018421:rifapentine