Pharmacokinetics
Absorption
The absolute bioavailability of afapentine has not been determined. The relative bioavailability (with an oral solution as a relavance 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 utapentine 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 on 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 (active metabolite on day 10 following oral administration of 600 mg rifapentine every 72 hours to healthy volunteers are contained in the following table.
|
Parameter |
Refapentine |
25-desacetyl Rifapentine |
| | Mean ± SD (n=12) |
|
Cmax (m g/mL) | 15.45 ± 4.62 | 6.26 ± 2.06 |
|
AUC (0-72h)( m g*h/mL) | 319.54 ± 91.52 | 215.88 ± 85.96 |
|
T ½ (h) | 13.19 ± 1.38 | 13.35 ± 2.67 |
|
T max (h) | 4.83 ± 1.80 | 11.25 ± 2.73 |
|
Clpo (L/h) | 2.03 ± 0.60 | -- |
Distribution
In a population pharmacokinet analysis in 351 tuberculosis patients who received 600 mg rifapentine in combination with bomazid, pyrazinamide and ethambutol, the estimated apparent volume of distribution was 70- 9: 1. In healthy volunteers, rifapentine and 25-desacetyl rifapentine were 97.7% and instead to plasma proteins, respectively. Rifapentine was mainly bound to albumin. Since extent of protein binding was observed in healthy volunteers, asymptomatic HIV-infected 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 esterasenzyme to form a microbiologically active 25-desacetyl rifapentine. Rifapentine and as 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 rifapentine, respectively. Based upon relative in vitro activities and AUC (0- ) values rifapentine and 25-desacetyl rifapentine potentially contributes 62% and 38% to the actual activities against M. tuberculosis, respectively.
Special Populations
Gender: In a population pharmacokmetics 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 pharmacokinetic 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 on healthy adults.
Renal Impaired Patients: The pharmacokinetics of rifapentine have not been evaluated in renal impaired patients. Although own 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 an 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 in SS. In a cross-study comparison, mean Cmax and AUC values of the 25-desacetyl metabolite 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: 33g protein, 55g fat, and 58 g carbohydrate) increases the mean AUC and Cmax of rifapentine observed under fasting conditions in asypromatic HIV-infected volunteers by about 51% and 53%, respectively.
Microbiology:
Mechanism of Action
Rifapentine, a cyclopentyl rifapentine, inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium ruberculosis 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 submit 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 10 to 10 bacilli. Due to the potential for resistance development to rifapentine, appropriate susceptibility tests should be performed in the event of persistently positive cultures.
M.tuberculosisorganisms 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 berween rifapentine and non-rifamycin antimycobacterial agents such as isoniazid and streptomycin.
In Vitro Activity of Rifapentine against M.tuberculosis
Rofapentine and its 25-desacetyl metabolite have demonstrated in vitro 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 therapeute 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 segmens. Animal studies have shown that the activity of rifapentine is influenced by dose and frequency of administration.
Susceptibility testing for Mycobacterium tuberculosis
Breakpoints to determune 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, isonized, 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, 317 patients who had received rifapentine in the Intensive Phase continued to receive rifapentine and isoniazid once weekly for upto 120 days. Three hundred tour 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.
The indication for treatment of pulmonary tuberculosis with PRIFTIN is based on the 6 month follow-up treatment outcome observed in Clinical Study 008 as a surrogate for the 2 year follow-up generally accepted as evidence of efficacy in the treatment of pulmonary tuberculosis.
| Table 2-1. Dose of Rifapentine,Rifampin, Isoniazid, Pyrazinamide, and Ethambutol |
| Rifapentine Combination Treatment |
| Intensive Phase | Rifapentine (mg) | Isoniazid (mg) | Pyrazinamide (mg) | Ethambutol (mg) |
| | Twice Weekly | Daily | Daily | Daily |
|
Brand Name: Priftin
Generic Name: Rifapentine
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