PRIFTIN®
(rifapentine)
150 mg Tablets

DESCRIPTION

PRIFTIN® (rifapentine) for oral administration contains 150 mg of the active ingredient rifapentine per tablet.

The 150 mg tablets also contain, as inactive ingredients: calcium stearate, disodium EDTA, FD&C Blue No. 2 aluminum lake, hydroxypropyl cellulose, hypromellose USP, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, propylene glycol, sodium ascorbate, sodium lauryl sulfate, sodium starch glycolate, synthetic red iron oxide, and titanium dioxide.

Rifapentine is a rifamycin derivative antibiotic and has a similar profile of microbiological activity to rifampin (rifampicin). The molecular weight is 877.04.

The molecular formula is C47H64N4O12.

The chemical name for rifapentine is rifamycin, 3-[[(4-cyclopentyl-1-piperazinyl)imino]methyl]-

or

3-[N-(4-Cyclopentyl-1-piperazinyl)formimidoyl] rifamycin or 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-cyclopentyl-l-piperazinyl)-formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate. It has the following structure:

ACTIONS/CLINICAL PHARMACOLOGY

Pharmacokinetics

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 to 6 hours after administration of the 600 mg rifapentine dose. Food (850 total calories: 33 g protein, 55 g fat and 58 g carbohydrate) increased AUC(0–∞) and Cmax by 43% and 44%, respectively over that observed when administered under fasting conditions. When oral doses of rifapentine were administered once daily or once every 72 hours to healthy volunteers for 10 days, single dose AUC(0–∞) value 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 600 mg. The pharmacokinetic characteristics of rifapentine and 25-desacetyl rifapentine (active metabolite) on day 10 following oral administration of 600 mg rifapentine every 72 hours to healthy volunteers are contained in the following table.

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 radiolabelled 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.

Special 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) 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 (Adolescents)

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

Renal Impaired Patients

The pharmacokinetics of rifapentine have not been eva luated 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). Since the elimination of these agents are primarily via the liver, the clinical significance of impaired hepatic function on the disposition of rifapentine and its 25-desacetyl metabolite is not known.

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 Cmax 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 Cmax and AUC values of the 25-desacetyl metabolite of 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 Cmax of rifapentine observed under fasting conditions in asymptomatic HIV-infected volunteers by about 51% and 53%, respectively.

Microbiology

Mechanism of Action

Rifapentine, a cyclopentyl rifamycin, 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.

Resistance Development

In the treatment of tuberculosis (see INDICATIONS AND USAGE), a small number of resistant cells present within large populations of susceptible cells can rapidly become predominant. Rifapentine resistance development in M. tuberculosis strains is principally due to one of several single point mutations that occur in the rpoB portion of the gene coding for the beta subunit of the DNA-dependent RNA polymerase. The incidence of rifapentine resistant mutants in an otherwise susceptible population of M. tuberculosis strains is approximately one in 107 to 108 bacilli. Due to the potential for resistance development to rifapentine, appropriate susceptibility tests should be performed in the event of persistently positive cultures.

M. tuberculosis organisms resistant to other rifamycins are likely to be resistant to rifapentine. A high level of cross-resistance between rifampin and rifapentine has been demonstrated with M. tuberculosis strains. Cross-resistance does not appear between rifapentine and non-rifamycin antimycobacterial agents such as isoniazid and streptomycin.

In Vitro Activity of Rifapentine against M. tuberculosis

Rifapentine and its 25-desacetyl metabolite have demonstrated in vitro activity against rifamycin-susceptible strains of Mycobacterium tuberculosis including cidal activity against phagocytized M. tuberculosis organisms grown in activated human macrophages.

In vitro results indicate that rifapentine MIC values for M. tuberculosis organisms are influenced by study conditions. Rifapentine MIC values were substantially increased employing egg-based medium compared to liquid or agar-based solid media. The addition of Tween 80 in these assays has been shown to lower MIC values for rifamycin compounds.

In mouse infection studies a therapeutic effect, in terms of enhanced survival time or reduction of organ bioburden, has been observed in M. tuberculosis-infected animals treated with various intermittent rifapentine-containing regimens. Animal studies have shown that the activity of rifapentine is influenced by dose and frequency of administration.

Susceptibility testing for Mycobacterium tuberculosis

Breakpoints to determine whether clinical isolates of M. tuberculosis are susceptible or resistant to rifapentine have not been established. The clinical relevance of rifapentine in vitro susceptibility test results for other mycobacterial species has not been determined.

CLINICAL TRIALS

A total of 722 patients were enrolled in Clinical Study 008, an open label, prospective, randomized, parallel group, active controlled trial, for the treatment of pulmonary tuberculosis. This population was mostly comprised of Black (>60%) or Multiracial (>31%) patients and the mean ± standard deviation age was 37 ± 11 years. Treatment groups were comparable with respect to age and race. The percentage of male patients was higher in the rifapentine combination group (80%) than in the rifampin combination group (73%). The study was divided into two phases on the basis of dosing frequency. For the first phase, designated as the Intensive Phase, 361 patients were randomized to receive rifapentine, isoniazid, pyrazinamide, and ethambutol for 60 days and 361 patients were randomized to receive rifampin, isoniazid, pyrazinamide, and ethambutol for 60 days. (Ethambutol was to be discontinued once baseline susceptibility test results were available.) Rifapentine and isoniazid were each administered at a fixed dose regardless of body weight. Rifampin, pyrazinamide, and ethambutol were administered based on body weight according to Table 2-1. Note: All drugs were administered daily in the Intensive Phase except for rifapentine which was administered twice weekly.

During the second phase, designated as the Continuation Phase, 321 patients who had received rifapentine in the Intensive Phase continued to receive rifapentine and isoniazid once weekly for up to 120 days. Three hundred seven patients who had received rifampin in the Intensive Phase continued to receive rifampin and isoniazid during the Continuation Phase twice weekly for up to 120 days. Rifampin and isoniazid were administered based on body weight according to Table 2-1.

Patients in either treatment group were scheduled to receive study drug over a 180-day period with a subsequent 24-month follow-up. Additionally, both treatment groups received pyridoxine (Vitamin B6) over the 180-day treatment period.