Safety and Pharmacokinetics of Escalating Daily Doses of the Antituberculosis Drug Rifapentine in Healthy Volunteers

Rifapentine (RPT) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RIF). The maximal tolerated daily dose of RPT and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose‐escalation s...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2012-05, Vol.91 (5), p.881-888
Main Authors: Dooley, K E, Bliven-Sizemore, E E, Weiner, M, Lu, Y, Nuermberger, E L, Hubbard, W C, Fuchs, E J, Melia, M T, Burman, W J, Dorman, S E
Format: Article
Language:English
Subjects:
Adult
Antitubercular Agents - administration & dosage
Area Under Curve
Biological and medical sciences
Cytochrome P-450 CYP3A - biosynthesis
Drug-Related Side Effects and Adverse Reactions
Female
Humans
Male
Medical sciences
Midazolam - pharmacokinetics
Middle Aged
Pharmacology. Drug treatments
Rifampin - administration & dosage
Rifampin - adverse effects
Rifampin - analogs & derivatives
Rifampin - pharmacokinetics
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Summary:Rifapentine (RPT) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RIF). The maximal tolerated daily dose of RPT 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 as a prespecified maximum of 20 mg/kg/day were well tolerated. Steady‐state RPT concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AUC0–24) and maximum concentration (Cmax) were similar in the 15‐ and 20‐mg/kg cohorts. Although RPT pharmacokinetics (PK) appeared to be time‐dependent, accumulation occurred with daily dosing. The mean AUC0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP3A) 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 RPT dose. In conclusion, RPT was tolerated at doses as high as 20 mg/kg/day, its PK were less than dose‐proportional, and its CYP3A induction was robust. Clinical Pharmacology & Therapeutics (2012); 91 5, 881–888. doi:10.1038/clpt.2011.323
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2011.323