Rifapentine

Rifapentine, a cyclopentyl rifamycin, is an antimycobacterial agent. Rifapentine inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis but not in mammalian cells. At therapeutic levels, rifapentine exhibits bactericidal activity against both intracellular and extracellular M. tuberculosis organisms. Both rifapentine and the 25-desacetyl metabolite accumulate in human monocyte-derived macrophages with intracellular/extracellular ratios of approximately 24:1 and 7:1, respectively.

When oral doses of rifapentine 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 AUC_ss(0–24h) or AUC_ss(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 600 mg. No plasma accumulation of rifapentine and 25-desacetyl rifapentine (active metabolite) is expected after once weekly administration of rifapentine.

The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine on day 10 following oral administration of 600 mg rifapentine every 72 hours to healthy volunteers are described in Table 1.

Table 1. Pharmacokinetics and Rifapentine and 25-Desacetyl Rifapentine in Healthy Volunteers:

The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine following single-dose oral administration of 900 mg rifapentine in combination with 900 mg isoniazid in fed conditions are described in Table 2.

Table 2. Mean ± SD Pharmacokinetic Parameters of Rifapentine and 25-Desacetyl Rifapentine in Healthy Volunteers When rifapentine is Coadministered with Isoniazid Under Fed Conditions (N=16):

^* Median (Min–Max).
^† Not Applicable.

Absorption

The absolute bioavailability of rifapentine has not been determined. The relative bioavailability (with an oral solution as a reference) of rifapentine 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 dose.

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

The administration of rifapentine (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 C_max and AUC, respectively. In contrast, the ingestion of the same meal decreased isoniazid C_max and AUC by 46% and of 23%, respectively.

Distribution

In a population pharmacokinetic analysis in 351 tuberculosis patients who received 600 mg rifapentine 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 C_max 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 in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent oral clearance of rifapentine 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 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).

Pediatric

In a pharmacokinetic study in pediatric patients (age 2 to 12 years), a single oral dose of 150 mg rifapentine was administered to those weighing less than 30 kg (n=11) and a single oral dose of 300 mg was administered to those weighing greater than 30 kg (n=12). The mean estimates of AUC and C_max were approximately 30% to 50% lower in these pediatric patients than those observed in healthy adults administered single oral doses of 600 mg and 900 mg.

A study compared the pharmacokinetics of rifapentine in pediatric patients (age 2 years to 11 years) with latent tuberculosis infection (n=80) receiving rifapentine once weekly based on weight (15 mg/kg to 30 mg/kg, up to a maximum of 900 mg) to that of adults (n=77) receiving rifapentine 900 mg once weekly. Children who could not swallow whole tablets were administered crushed tablets mixed in soft food. Overall, the geometric mean AUC of rifapentine in this age group was 31% higher compared to adult patients receiving 900 mg rifapentine once weekly (720 versus 551 mcg∙h/mL). The geometric mean AUC of rifapentine was 60% higher in children administered whole tablets (884 versus 551 mcg∙h/mL) and 19% higher in children administered crushed tablets (656 versus 551 mcg∙h/mL), as compared to exposures in adults. Pediatric patients administered crushed rifapentine tablets had 26% lower rifapentine exposures compared to those pediatric patients who were given whole tablets.

Population pharmacokinetic analysis showed that rifapentine clearance adjusted to body weight decreased with increasing age of pediatric patients (2 to 18 years).

In another pharmacokinetics study of rifapentine in healthy adolescents (age 12 to 15 years), 600 mg rifapentine was administered to those weighing ≥45 kg (n=10) and 450 mg was administered to those weighing less than 45 kg (n=2). The pharmacokinetics of rifapentine was similar to those observed in healthy adults.

Renal Impaired Patients

The pharmacokinetics of rifapentine has not been evaluated in renal impaired patients. Although only about 17% of an administered dose is excreted via the kidneys, the clinical significance of impaired renal function on the disposition of rifapentine and its 25-desacetyl metabolite is not known.

Hepatic Impaired Patients

Following oral administration of a single 600 mg dose of rifapentine to mild to severe hepatic impaired patients (n=15), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar in patients with various degrees of hepatic impairment and to that observed in another study for healthy volunteers (n=12).

Asymptomatic HIV-Infected Volunteers

Following oral administration of a single 600 mg dose of rifapentine to asymptomatic HIV-infected volunteers (n=15) under fasting conditions, mean C_max and AUC_(0–∞) of rifapentine were lower (20%–32%) than that observed in other studies in healthy volunteers (n=55). In a cross-study comparison, mean C_max and AUC values of the 25-desacetyl rifapentine, when compared to healthy volunteers were higher (6%–21%) in one study (n=20), but lower (15%–16%) in a different study (n=40). The clinical significance of this observation is not known. Food (850 total calories: 33 g protein, 55 g fat, and 58 g carbohydrate) increases the mean AUC and C_max of rifapentine observed under fasting conditions in asymptomatic HIV-infected volunteers by about 51% and 53%, respectively.

Drug-Drug Interactions

Isoniazid

Coadministration of rifapentine (900 mg single dose) and isoniazid (900 mg single dose), in fasted condition, did not result in any significant change in the exposure of rifapentine and isoniazid compared to when administered alone in fasted condition.

Rifapentine is an inducer of cytochrome P450 3A4 and 2C8/9. Therefore, it may increase the metabolism and decrease the activity of other coadministered drugs that are metabolized by these enzymes. Dosage adjustments of the coadministered drugs may be necessary if they are given concurrently with rifapentine.

Indinavir

In a study in which 600 mg rifapentine was administered twice weekly for 14 days followed by rifapentine twice weekly plus 800 mg indinavir 3 times a day for an additional 14 days, indinavir C_max decreased by 55% while AUC reduced by 70%. Clearance of indinavir increased by 3-fold in the presence of rifapentine while half-life did not change. But when indinavir was administered for 14 days followed by coadministration with rifapentine for an additional 14 days, indinavir did not affect the pharmacokinetics of rifapentine.

Fixed-dose combination of efavirenz, emtricitabine and tenofovir

Once-weekly coadministration of 900 mg rifapentine with the antiretroviral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg in HIV-infected patients did not result in any substantial change in steady state exposures of efavirenz, emtricitabine, and tenofovir (Table 3). A 15% decrease in efavirenz C_min and AUC and a 13% decrease in tenofovir C_min were observed with repeated weekly doses of rifapentine (Table 3). No clinically significant change in CD4 cell counts or viral loads were noted.

Table 3. Treatment Ratio Estimates (with versus without repeated once-weekly Rifapentine 900 mg) with 90% Confidence Intervals for Efavirenz, Emtricitabine and Tenofovir Pharmacokinetic Parameters: