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Clin Pharmacol Ther. 2012 May;91(5):881-8. doi: 10.1038/clpt.2011.323.

Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers.

Author information

1
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. kdooley1@jhmi.edu

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.

PMID:
22472995
PMCID:
PMC3837382
DOI:
10.1038/clpt.2011.323
[Indexed for MEDLINE]
Free PMC Article

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