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Mechanism of Action
Rifapentine, a cyclopentyl rifamycin, is an antimycobacterial agent [see Microbiology].
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.
The administration of rifapentine with a high fat meal (850 total calories: 33 g protein, 55 g fat and 58 g carbohydrate) increased AUC(0-ro) 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-ro) 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 parameters 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 Table 3.
Table 3. Pharmacokinetics and rifapentine and 25-desacetyl rifapentine in healthy volunteers.
|Mean ± SD (n=12)|
|Cmax (μg/mL)||15.05 ± 4.62||6.26 ± 2.06|
|AUC (0-72h)(μg*h/mL)||319.54 ± 91.52||215.88 ± 85.96|
|T½(h)||13.19 ± 1.38||13.35 ± 2.67|
|Tmax (h)||4.83 ± 1.80||11.25 ± 2.73|
|Clpo (L/h)||2.03 ± 0.60||--|
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.
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-ro) 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-ro) values, rifapentine and 25-desacetyl rifapentine potentially contributes 62% and 38% to the clinical activities against M. tuberculosis, respectively.
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 pharmacokinetic study in pediatric patients (age 2 to 12 years), a single oral dose of 150 mg rifapentine was administered to those weighing <30 kg (n=11) and a single oral dose of 300 mg was administered to those weighing >30 kg (n=12). The mean estimates of AUC and Cmax 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.
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 <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 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). 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-ro) 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.
Rifapentine is an inducer of cytochrome P4503A4 and 2C8/9. Therefore, it may increase the metabolism and decrease the activity of other co-administered drugs that are metabolized by these enzymes. Dosage adjustments of the co-administered drugs may be necessary if they are given concurrently with rifapentine [see DRUG INTERACTIONS].
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 Cmax 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 [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
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.
In Vitro Activity
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.
The correlation between rifapentine MICs and clinical cure has not been established. Interpretive criteria/breakpoints to determine whether clinical isolates of M. tuberculosis are susceptible or resistant to rifapentine have not been established.
In Vivo Activity
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.
In the treatment of tuberculosis, 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.
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.
Rifapentine was studied in two randomized, open-label controlled clinical trials.
The first trial was an open-label, prospective, parallel group, active controlled trial in patients with pulmonary tuberculosis, excluding those with HIV-infection. The population was mostly comprised of Black (> 60%) or Multiracial (>31%) patients. Treatment groups were comparable for age and sex and consisted primarily of male subjects with a mean age of 37 ± 11 years. In the initial 2 month phase of treatment (60 days), 361 patients received rifapentine 600 mg twice a week in combination with daily isoniazid, pyrazinamide, and ethambutol and 361 subjects received rifampin 600 mg in combination with isoniazid, pyrazinamide and ethambutol all administered daily. The doses of the companion drugs were the same in both treatment arms during the initial phase: isoniazid 300 mg, pyrazinamide 2000 mg, and ethambutol 1200 mg. For patients weighing less than 50 kg, the doses of rifampin (450 mg), pyrazinamide (1500 mg) and ethambutol (800 mg) were reduced. Ethambutol was discontinued when isoniazid and rifampin susceptibility testing results were confirmed. During the 4 month continuation phase, 321 patients in the rifapentine group continued to receive rifapentine 600 mg dosed once weekly with isoniazid 300 mg and 307 patients in the rifampin arm received twice weekly rifampin and isoniazid 900 mg. For patients weighing less than 50 kg, the doses of rifampin (450 mg) and isoniazid (600 mg) were reduced. Both treatment groups received pyridoxine (Vitamin B6) over the 6 month treatment period. Treatment was directly observed. Despite observed therapy, 65/361 (18%) of patients in the rifapentine arm and 34/361 (9%) in the rifampin arm received overdoses of one or more of the administered study medications during the initial or continuation phase of treatment. Only seven of these patients had adverse reactions reported with the overdose (5 in the rifapentine group and 2 in the rifampin group).
Table 4 below contains assessments of sputum conversion at end of treatment (6 months) and relapse rates at the end of follow-up (24 months).
Table 4. Clinical Outcome in HIV Negative Patients with Pulmonary Tuberculosis
|Rifapentine Combination Treatment % and (n/N*)||Rifampin Combination Treatment % and (n/N*)|
|Status at End of 6 months of Treatment|
|Converted||87% (248/286)||80% (226/283)|
|Not Converted||1% (4/286)||3% (8/283)|
|Lost to Follow-up||12% (34/286)||17% (49/283)|
|Status Through 24 Month Follow-up**:|
|Relapsed||12% (29/248)||7% (15/226)|
|Sputum Negative||57% (142/248)||64% (145/226)|
|Lost to Follow-up||31% (77/248)||29% (66/226)|
| * All data for patients with confirmed susceptible M. tuberculosis (rifapentine combination treatment, N=286; rifampin combination treatment, N=283). |
** Twenty-two (22) deaths occurred during the study; 11 in each treatment arm
Risk of relapse was greater in the group treated with the rifapentine combination. Higher relapse rates were associated with a lower rate of compliance with the companion antituberculosis drugs as well as a failure to convert sputum cultures at the end of the initial 2 month treatment phase. Relapse rates were also higher for males in both regimens. Relapse in the rifapentine group was not associated with development of mono-resistance to rifampin.
In vitro susceptibility testing was conducted against M. tuberculosis isolates recovered from 620 patients enrolled in the study. Rifapentine and rifampin MIC values were determined employing the radiometric susceptibility testing method utilizing 7H12 broth at pH 6.8 (CLSI procedure m24-A; (1)). Six hundred and twelve patients had M. tuberculosis isolates that were susceptible to rifampin (MIC < 0.5 p,g/ml). Of these patients, six hundred and ten had M. tuberculosis isolates (99.7%) with rifapentine MICs of < 0.125 p,g/ml. The other two patients that had rifampin susceptible M. tuberculosis isolates had rifapentine MICs of 0.25 μg/ml. The remaining eight patients had M. tuberculosis isolates that were resistant to rifampin (MIC > 8.0 p,g/ml). These M. tuberculosis isolates had rifapentine MICs of > 8.0 p,g/ml. In this study high rifampin and rifapentine MICs were associated with multi-drug resistant M. tuberculosis (MDRTB) isolates. Rifampin monoresistance was not observed in either treatment arm. This information is provided for comparative purposes only as rifapentine breakpoints have not been established.
The second trial was a randomized, open-label trial in 1075 HIV seronegative and seropositive patients with pulmonary tuberculosis. Patients with culture-positive, drug-susceptible pulmonary tuberculosis who had completed the initial 2 month phase of treatment with 4 drugs (rifampin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) under direct observation were randomly assigned to receive either rifapentine 600 mg and isoniazid 15 mg/kg (max 900 mg) once weekly or rifampin 10 mg/kg (max 600 mg) and isoniazid 15 mg/kg (max 900 mg) twice weekly for the 4 month continuation phase. Study drugs were given under direct observation therapy in both arms.
In the rifapentine arm, 502 HIV seronegative and 36 HIV seropositive patients were randomized and in the rifampin arm 502 HIV seronegative and 35 HIV seropositive patients were randomized to treatment. Enrollment of HIV seropositive patients was stopped when 4 of 36 patients in the rifapentine combination group developed rifampin monoresistance.
Table 5 below contains assessments of sputum conversion at the end of treatment (6 months total: 2 months of initial and 4 months of randomized continuation treatment) and relapse rates at the end of follow-up (24 months) in all HIV seronegative patients randomized to treatment. The failure and relapse rates reported in this study could be underestimated due to the limitation of the microbiologic methods used in the study. Positive culture was based on either one sputum sample with >10 colonies on solid media OR at least 2 positive sputum samples on liquid or solid media. However, only one sputum sample was collected at each visit in a majority of patients.
Table 5: Clinical Outcome in HIV Negative Patients with Pulmonary Tuberculosis
|Rifapentine Combination Treatment % (n/N)||Rifampin Combination Treatment % (n/N)|
|Status at End of 4 Months Continuation Phase|
|Treatment Response *||93.8% (471/502)||91.0% (457/502)|
|Not Converted||1.0% (5/502)||1.2% (6/502)|
|Did Not Complete Treatment**||4.2% (21/502)||7.0% (35/502)|
|Deaths||1.0 % (5/502)||0.8% (4/502)|
|Status Through 24 Month Follow-up:|
|Relapsed||8.7% (41/471)||4.8% (22/457)|
|Sputum Negative||79.4% (374/471)||80.1% (366/457)|
|Lost to Follow-up||7.9% (37/471)||9.8% (45/457)|
|Deaths||4.0% (19/471)||5.3% (24/457)|
| * Treatment response was defined as subjects who responded successfully after 16 doses of rifampin and isoniazid or after 8 doses of rifapentine and isoniazid, and remained sputum negative through the end of continuation phase therapy. |
** Due to drug toxic effects, non-adherence, withdrawal of consent, receipt of nonstudy regimen, other.
Higher relapse rates in HIV seronegative patients were seen in patients with a positive sputum culture at 2 months (i.e., at the time of study randomization), cavitation on chest x-ray, and bilateral pulmonary involvement.
Seventy-one HIV seropositive patients were enrolled into the study. There were no treatment failures during the study phase therapy. Sixty-one patients completed therapy and were assessed for relapse. The rates of relapse were 16.7% (5/30) in the rifapentine group and 9.7% (3/31) in the rifampin group.
Risk factors that predisposed to relapse in the HIV seropositive patients included the presence of both pulmonary and extrapulmonary disease at baseline, low CD4 counts, use of azole antifungals and younger age.
In HIV seropositive patients, 4 of the 5 relapses from the rifapentine combination group involved M. tuberculosis strains with rifampin monoresistance (RMR). No relapse strain in the twice weekly rifampin/isoniazid group had acquired drug resistance. These data are consistent with other documented acquired rifampin monoresistance in HIV seropositive adults who fail or relapse after treatment with intermittent regimens with isoniazid and other rifamycins (rifampin and rifabutin).
The death rate among all study participants did not differ between the two treatment groups.
1. Clinical and Laboratory Standards Institute. m24-A Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard. 23 ed. 2003. Clinical Laboratory Standards Institute, Wayne, PA
Last reviewed on RxList: 8/27/2010
This monograph has been modified to include the generic and brand name in many instances.
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