Rifapentine clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
Clinical Pharmacology
Mechanism of Action
Rifapentine, a cyclopentyl rifamycin, is an antimycobacterial agent [see Clinical Pharmacology, Microbiology ].
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.
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–∞) 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 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 .
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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 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 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–∞) 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.
Drug-Drug Interactions
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 ].
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 ].[1]
References
Adapted from the FDA Package Insert.