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.

Figure 1

Participant flow in Tuberculosis Trials Consortium Study 29B. PK, pharmacokinetics.

Figure 2

Single-dose and multiple-dose rifapentine (RPT) and desacetylrifapentine (desRPT) concentrations. (a) Mean plasma RPT concentrations (μg/ml) vs. time after single doses of 5 mg/kg (open triangles), 10 mg/kg (open circles), 15 mg/kg (filled circles), or 20 mg/kg (filled squares). (b) Mean plasma RPT concentrations vs. time after 14 daily doses of 5 mg/kg (open triangles), 10 mg/kg (open circles), 15 mg/kg (filled circles), or 20 mg/kg (filled squares). (c) Mean plasma desRPT concentrations vs. time after single doses of 5 mg/kg (open triangles), 10 mg/kg (open circles), 15 mg/kg (filled circles), or 20 mg/kg (filled squares) of RPT. (d) Mean plasma desRPT concentrations vs. time after 14 daily doses of 5 mg/kg (open triangles), 10 mg/kg (open circles), 15 mg/kg (filled circles), or 20 mg/kg (filled squares) of RPT. The values shown represent arithmetic means with SE bars.

Figure 3

Mean (SD) values of (a) C_max and (b) AUC_0–12 of midazolam (MDZ) and 1-OH-midazolam (OH-MDZ) when oral MDZ (15 mg) is coadministered with steady-state rifampin (RIF) or rifapentine (RPT), expressed as percentages of the respective concentrations when MDZ (15 mg) is administered alone. AUC, area under the concentration–time curve; C_max, maximum concentration.

Figure 4

Schematic of the dosing regimen and sample collection for pharmacokinetic testing.