Rifapentine 150 mg · Tablets

Rifapentine, a cyclopentyl rifamycin, is an antimycobacterial agent [see Microbiology (12.4)].

When oral doses of rifapentine tablets were administered once daily or once every 72 hours to healthy volunteers for 10 days, single dose AUC (0-∞) of rifapentine was similar to its steady-state

AUCss (0-24h) or AUCss (0-72h) values, suggesting no significant auto-induction effect on steady-state pharmacokinetics of rifapentine. Steady-state conditions were achieved by day 10 following daily administration of rifapentine tablets 600 mg. No plasma accumulation of rifapentine and 25-desacetyl rifapentine (active metabolite) is expected after once weekly administration of rifapentine tablets.

The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine on day 10 following oral administration of 600 mg rifapentine tablets every 72 hours to healthy volunteers are described in Table 5.

The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine following single-dose oral administration of 900 mg rifapentine tabletsin combination with 900 mg isoniazid in fed conditions are described in Table 6.

Absorption — The absolute bioavailability of rifapentine tablets has not been determined. The relative bioavailability (with an oral solution as a reference) of rifapentine tablets after a single 600 mg dose to healthy adult volunteers was 70%. The maximum concentrations were achieved from 5 hours to 6 hours after administration of the 600 mg rifapentine tablets dose.

The administration of rifapentine tablets with a high fat meal increased rifapentine Cmax and AUC by 40% to 50% over that observed when rifapentine tablets were administered under fasting conditions.

The administration of rifapentine tablets(900 mg single dose) and isoniazid (900 mg single dose) with a low fat, high carbohydrate breakfast, led to a 47% and 51% increase in rifapentine Cmax and AUC, respectively. In contrast, the ingestion of the same meal decreased isoniazid Cmax and AUC by 46% and of 23%, respectively.

Distribution — In a population pharmacokinetic analysis in 351 tuberculosis patients who received 600 mg rifapentine tablets in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent volume of distribution was 70.2 ± 9.1 L. In healthy volunteers, rifapentine and 25-desacetyl rifapentine were 97.7% and 93.2% bound to plasma proteins, respectively. Rifapentine was mainly bound to albumin. Similar extent of protein binding was observed in healthy volunteers, asymptomatic HIV-infected subjects and hepatically impaired subjects.

Metabolism/Excretion — Following a single 600 mg oral dose of radiolabeled rifapentine to healthy volunteers (n=4), 87% of the total 14C-rifapentine was recovered in the urine (17%) and feces (70%). Greater than 80% of the total 14C-rifapentine dose was excreted from the body within 7 days. Rifapentine was hydrolyzed by an esterase enzyme to form a microbiologically active 25-desacetyl rifapentine. Rifapentine and 25-desacetyl rifapentine accounted for 99% of the total radioactivity in plasma. Plasma AUC(0-∞) and Cmax values of the 25-desacetyl rifapentine metabolite were one-half and one-third those of the rifapentine, respectively. Based upon relative in vitro activities and AUC(0-∞) values, rifapentine and 25-desacetyl rifapentine potentially contributes 62% and 38% to the clinical activities against M. tuberculosis, respectively.

Specific Populations — Gender: In a population pharmacokinetics analysis of sparse blood samples obtained from 351 tuberculosis patients who received 600 mg rifapentine tablets in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent oral clearance of rifapentine tablets for males and females was 2.51 ± 0.14 L/h and 1.69 ± 0.41 L/h, respectively. The clinical significance of the difference in the estimated apparent oral clearance is not known.

Elderly: Following oral administration of a single 600 mg dose of rifapentine tablets to elderly (65 years and older) male healthy volunteers (n=14), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar to that observed for young (18 to 45 years) healthy male volunteers (n=20).