Priftin

Priftin Mechanism of Action

rifapentine

Manufacturer:

Sanofi-Aventis

Distributor:

DKSH
Full Prescribing Info
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Rifapentine belongs to the rifamycin class of antibiotics which exert their antibacterial action by selectively inhibiting the DNA-dependent RNA polymerase of susceptible bacteria.
It forms a stable complex with bacterial DNA-dependent RNA polymerase, leading to repression of RNA synthesis and cell death.
Rifapentine and its 25-desacetyl metabolite accumulate in human monocyte-derived macrophages and are bactericidal to both intracellular and extracellular Mycobacterium tuberculosis organisms at concentrations achievable by the recommended oral dosing regimens. 25-desacetyl rifapentine, the active metabolite, is almost as active as rifapentine.
In vitro studies showed rifapentine to be highly concentrated within cells after brief incubation periods in media containing the antibiotic.
Clinical Efficacy/Clinical Studies:
Summary of the TBTC-S26 Phase 3 clinical study: The pivotal TBTC-S26 study was a multicenter, prospective, randomized, open-label trial conducted among more than 8000 high-risk tuberculin skin test (TST) reactors (i.e., household and other close contacts of active tuberculosis cases, recent [within 2 years] tuberculin converters, persons with fibrotic lesions on chest X-ray [CXR], HIV-infected persons, and young children), who required treatment of latent tuberculosis infection (LTBI) to prevent tuberculosis (TB) disease. Close contacts were defined as persons spending ≥ 4 hours in a shared airspace during a 1-week period with a person with sputum culture-confirmed TB disease. This included household and non-household contacts. In group settings such as households, group homes, or shelters, all patients were placed on the same regimen as the first patient in the group i.e., clusters. Close contacts were randomized by household (clusters); others were randomized individually.
The primary objective of the study was to evaluate the effectiveness of weekly rifapentine in combination with isoniazid for 3 months (3RPT/INH) given by directly-observed therapy (DOT) versus daily self-administered isoniazid for 9 months (9INH) in preventing TB disease in high-risk tuberculin reactors. In addition to the main study, two sub-studies one each in pediatric population (2 - 17 years) and HIV-infected patients with LTBI at high risk of progression to active TB disease were nested in the main study and continued beyond the completion of enrollment in the main study to recruit additional patients in these subgroups. (See Table 1.)

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The primary endpoint used to determine effectiveness was the development of active TB disease confirmed by sputum culture for M. tuberculosis in adults (i.e., ≥ 18 years of age) and culture-confirmed or clinical TB disease in children less than 18 years of age, at 33 months after enrollment in the study.
Table 2 shows that in the modified intention-to-treat (MITT) analysis for the main study, TB disease developed in 7 of 3986 patients in the 3RPT/INH group (cumulative rate, 0.19%) versus 15 of 3745 patients in 9INH group (cumulative rate, 0.43%), for a difference of 0.24 percentage points.
Rates of treatment completion were 82.1% in the 3RPT/INH group and 69.0% in the 9INH group (p<0.001). Rates of permanent drug discontinuation due to an adverse event were 4.9% in the 3RPT/INH and 3.7% in the INH therapy group (p = 0.009). (See Table 2.)

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The incidence of drug resistance was low and similar between the 2 treatment groups. In the 9INH treatment group, 2 cases were found to be INH-monoresistant. Both cases developed in patients with unknown HIV status. In the 3RPT/INH treatment group, 1 case was found to be RIF- and PZA-resistant, INH-susceptible M. bovis infection. This case was reported in a patient with HIV infection who had treatment interruptions and completed therapy late. Another case in the 3RPT/INH treatment group was found to be PZA monoresistant.
Pediatric Sub-study: RPT dosing in 12 to 17 year-old children enrolled in the 3RPT/INH group was identical to adults (12 weekly doses of RPT 900 mg or 750 mg if less than 50 kg). For children aged 2 to 11 years, the dose of RPT given in combination with INH was based on the weight at enrollment (see Table 1) without exceeding 900 mg. The dose of INH in the 3RPT/INH arm was adjusted for age: 15 mg/kg for children ≥12 years old (rounded up to nearest 50 or 100 mg; 900 mg maximum) and 25 mg/kg for those 2 to -11 years (rounded up to nearest 50 or 100 mg; 900 mg maximum). The dose of INH in the 9INH group was: 5 mg/kg for children ≥12 years old (rounded up to nearest 50 or 100 mg, 300 mg maximum) and 10-15 mg/kg for those 2 to -11 years (rounded up to nearest 50 or 100 mg, 300 mg maximum).
Approximately 67% of the enrolled children were included in the analysis for the LTBI main study. Three children in the 9INH group developed tuberculosis (Table 3) including one INH-monoresistant, there were no TB cases reported in the 3RPT/INH. The treatment completion rate in the MITT population was statistically significantly higher among children in the 3RPT/INH group than in children in the 9INH group: 88.1% versus 81.0%, respectively, (p=0.003). (See Table 3.)

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HIV substudy: In the HIV substudy MITT population at 33 months after study enrollment, TB disease developed in 2 of 206 patients in the 3RPT/INH group (cumulative rate, 1.01%) and in 6 of 193 patients in the 9INH group (cumulative rate, 3.50%), for a difference of -2.49% with an upper limit of the 95% CI of +0.60% . The TB event rate in the HIV substudy was higher than that observed in the main study, which included mostly non-infected patients (see Table 4). Four of the 8 HIV-infected patients who developed TB (2 patients in the 3RPT/INH group including one PZA-Rif resistant strain and 2 patients in the 9INH group) were enrolled in the main study and are also included in the results for the main study. One patient in the 9INH group developed a multiresistant TB (RIF-INH-Streptomycin) during the extension phase. The treatment completion rate was statistically significantly higher among HIV-infected patients in the 3RPT/INH group than in the 9INH HIV-infected patients: 88.8% versus 63.7%, respectively, (p≤0.0001). (See Table 4.)

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Pharmacokinetics: When 600 mg oral doses of rifapentine were administered once daily or once every 72 hours to healthy volunteers for 10 days (4 doses), mean Cthrough were below the limit of quantification suggesting no accumulation, moreover single dose AUC (0-∞) of rifapentine was similar to its AUCss(0-72h) values after 4 repeated dose, suggesting no significant auto-induction effect.
Based on the data observed after a single oral dose of 900 mg in healthy subjects, no plasma accumulation of rifapentine and 25-desacetyl rifapentine (active metabolite) is expected after once weekly administration of Priftin.
The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine on day 10 following oral administration of 600 mg Priftin every 72 hours to healthy volunteers are described in Table 5. (See Table 5.)

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The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine following single-dose oral administration of 900 mg Priftin in combination with 900 mg isoniazid in fed conditions are described in Table 6. (See Table 6.)

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Absorption: The absolute bioavailability of rifapentine has not been determined. Based on mass balance study, absorption was estimated as almost complete.
Rifapentine bioavailability is affected by food.
When the tablet is administered with food the bioavailability of rifapentine and its active metabolite increases by 40% to 50%. This increase in bioavailability is not affected by the meal composition including the amount of lipids. Rifapentine should be taken with food in order to maximize rifapentine and 25-desacetyl rifapentine exposures and reduce inter-subject variability.
In contrast, the ingestion of the meal decreases isoniazid exposures (Cmax and AUC by 46% and of 23%, respectively with the low fat, high carbohydrate breakfast).
Distribution: In healthy volunteers, rifapentine and 25-desacetyl rifapentine were highly 97.7% and 93.2% bound to plasma proteins, respectively. Similar extent of protein binding was observed in healthy volunteers, asymptomatic HIV-infected subjects and hepatically impaired subjects.
Following oral dosing of rifapentine in fed condition, the apparent volume of distribution is 32 L.
The intrapulmonary distribution was studied in healthy subjects who received a single oral dose of rifapentine (600 mg). The peak concentrations in plasma, in epithelial lining fluid, and in alveolar cells were 26.2, 3.7, and 5.3 µg/mL, respectively. Although the intrapulmonary RPT concentrations were less than the plasma RPT concentrations at all time periods, they remained above the RPT and 25-DRPT MIC for the 48-h observation period.
Metabolism: Rifapentine was hydrolyzed by an esterase enzyme to form a single microbiologically active metabolite 25-desacetyl rifapentine.
This metabolite represents 60 to 70% of rifapentine AUC.
Elimination:After administration of 14C-rifapentine, the majority of the dose is excreted in feces (70%), while urine is a minor pathway for excretion (17%). Oral plasma clearance of rifapentine is low with values in the range of 1.5 to 2 L/h. The apparent elimination of rifapentine and 25-desacetyl rifapentine are monophasic with a terminal half-life ranging from 13 to 17h.
The main elimination pathways are metabolism for rifapentine and biliary excretion in feces for both rifapentine and its metabolite 25-desacetyl rifapentine. Renal clearance is a minor pathway of excretion for rifapentine and its metabolite.
Drug Interactions: Potential of rifapentine to affect other drugs: Cytochromes P450 substrates: In vitro, rifapentine and its metabolite (25-desacetyl-rifapentine) are potent inducer of CYP3A4. In vivo in human, rifapentine has also been shown to be a potent CYP3A4 inducer: rifapentine daily (from 5 mg/kg) decreased midazolam exposure by 90%, rifapentine 600 mg twice weekly dosing reduced indinavir (protease inhibitor substrate of CYP3A4) exposure by 70%. There is no clinical data evaluating drug-drug interaction between CYP3A substrate and rifapentine at dosing regimen recommended for LTBI (900 mg weekly dosing). However, rifapentine is also predicted a potent inducer at this dosing regimen.
In vitro, rifapentine is an inducer of CYP2C8 and CYP2C9 and its metabolite (25-desacetyl-rifapentine) is a potential inhibitor of CYP2C8. No clinical interaction study was performed to assess in vivo potential of RPT to interact with drugs metabolized by CYP2C8/C9 but the risk of interaction is likely. The in vivo net effect, resulting from induction and inhibition of CYP2C8 was not evaluated but a higher impact of induction can be predicted.
In vitro studies showed that rifapentine and its metabolite (25-desacetyl-rifapentine) are inducers of CYP2B6 and that rifapentine is an inhibitor of CYP2B6. Interaction with CYP2B6 substrate was evaluated in one clinical study with efavirenz which is known as a very sensitive CYP2B6 substrate. After a single and repeated weekly administration of rifapentine 900 mg, no or minor modification (≤15%) of steady-state exposure of efavirenz was observed.
In vitro, rifapentine and its metabolite are not inducer of CYP1A2.
Based on in vitro data, it is predicted that rifapentine and its metabolite have no potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP2E1, in vivo in human.
Transporter substrates: In vitro, rifapentine has been shown to inhibit several transporters (P-gp, BCRP and OATP1B1/B3, OCT1). However, the risk of clinically significant interaction resulting from inhibition of BCRP, OATP1B1/B3, evaluated using a mechanistic static approach, was considered as minimal. Moreover, rifamycins are known to induce some of these transporters (such as P-gp, OATP1B1/OATP1B3) via activation of PXR and could balance the inhibition effect. For P-gp, interactions have been evaluated in human with 2 substrates of P-gp, raltegravir and tenofovir suggesting a limited effect.
However, because of narrow therapeutic index of digoxin (P-gp substrate), appropriate monitoring and dose adjustment of digoxin may be necessary in case of co-administration with rifapentine (see Interactions).
Potential of other drugs to affect rifapentine: Rifapentine is metabolized by esterases and its main metabolite, 25-desacetyl-rifapentine, is not metabolized. There is lack of risk of interaction with CYP450 inducer and as well as inhibitor drugs (such as triazole antifungal agents frequently coadministered in HIV-infected patients). Similarly, taking into account the high passive diffusion component in the hepatocyte uptake or the good intestinal permeability, potential drug interaction with transporters inhibitor/inducer drugs are not expected.
Special Populations: Gender: PK profiles in healthy young women and young men did not evidence any gender effect for rifapentine or 25-desacetyl-rifapentine.
Gender was also investigated as covariates of population PK model and was not associated with rifapentine PK variability.
Elderly patients: In elderly (≥ 65 years), following single oral administration of 600 mg, mean rifapentine and 25-desacetyl-rifapentine exposures were increased (41% for rifapentine AUC, 58% for 25-desacetyl-rifapentine) compared to healthy young subjects (historical comparison). However no dose adjustments were recommended for elderly subjects based on safety results in elderly healthy subjects and elderly patients with LTBI.
Pediatric patients: In healthy adolescents, rifapentine and 25-desacetyl-rifapentine PK were not different from those observed in healthy adults.
In pediatrics (younger than 12-years old), a significant correlation was observed between clearance and age: clearance adjusted to body weight increased when decreasing age.
Based on these findings, a weight band dosing (Table 7) was selected for rifapentine in children with LTBI and validated with PK and safety data in this population.
In children (2 - 12 years of age) receiving doses based on weight , while the mean rifapentine dosages in mg/kg were 2-fold higher than in adults (23 versus 11 mg/kg), exposures were 31% and 41% higher than adults for rifapentine and 25-desacetyl-rifapentine respectively, exposures that in adults have been associated with successful treatment of LTBI. Among children, exposure was about 25% lower in those who could not swallow the whole tablets and received crushed tablets but still higher than in adults. Despite the generally increased exposure observed in children, higher mg/kg Priftin doses were well tolerated.
Hepatic impairment: Following oral administration of a single 600 mg dose of Priftin to mild to severe hepatic impaired patients, the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar in patients with various degrees of hepatic impairment. In comparison to healthy subjects, rifapentine and 25-desacetyl-rifapentine exposure (AUC) were increased in subjects with hepatic impairment by 19% to 25% and 77%to 99%, respectively.
Renal impairment: The pharmacokinetics of rifapentine have not been evaluated in renal impaired patients. However, the risk of an impact of impaired renal function on PK is considered as minimal 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.
Asymptomatic HIV-Infected Volunteers: In asymptomatic HIV-infected subjects, rifapentine and 25-desacetyl metabolite PK profiles were not significantly different from those observed in healthy subjects. The safety and PK results indicated that no dose adjustment for Priftin is necessary for asymptomatic HIV-infected patients.
Toxicology: Preclinical Safety Data: Carcinogenicity: A two-year carcinogenicity in NMRI mice (Harlan Winklemann) was carried out with rifapentine at oral dose levels of 5, 20 and 80 mg/kg/d. At histological examination, a statistically significant higher incidence of hepatocellular carcinomas was seen in all treated male groups, but not in females. Dose-related pre-neoplastic eosinophilic foci of hepatocellular alterations were also detected in mid and high dose males. In addition, treatment-related centrilobular fatty changes occurred in high dose males. Rifapentine elicits an increase of the number of both liver tumors and altered cell foci in the mouse. Overall, it is assumed that rifapentine causes liver tumors in mice through a mechanism, which is not relevant to humans.
A two-year carcinogenicity study was carried out in Wistar rats with rifapentine at the dose levels of 2.5, 10 and 40 mg/kg/d. Tumors were limited to nasal turbinates and were all benign in nature. Because observed tumors location was limited to nasal cavity, were exclusively benign in nature and because of the specificities of nasal turbinates in the rat, it is considered that RPT-induced higher (than control) incidence of nasal adenomas is a rat specific effect.
Genotoxicity: A whole battery of in vitro and in vivo tests was carried out, both with rifapentine and with 25-DRPT. All data taken together – gene mutation in bacteria or eukaryote cells, chromosomal aberration tests or in vivo assays - it was concluded that both rifapentine and its human metabolite 25-DRPT do not represent a genotoxic risk to humans.
Rifapentine was negative in the following genotoxicity tests: in vitro gene mutation assay in bacteria (Ames test); in vitro point mutation test in Aspergillus nidulans; in vitro gene conversion assay in Saccharomyces cerevisiae; host-mediated (mouse) gene conversion assay with Saccharomyces cerevisiae; in vitro Chinese hamster ovary cell/hypoxanthineguanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay; in vitro chromosomal aberration assay utilizing rat lymphocytes; and in vivo mouse bone marrow micronucleus assay.
The 25-desacetyl metabolite of rifapentine was positive in the in vitro mammalian chromosome aberration test in V79 Chinese Hamster cells, but was negative in the in vitro gene mutation assay in bacteria (Ames test), the in vitro Chinese hamster ovary cell/hypoxanthine-guanine- phosphoribosyl transferase (CHO/HGPRT) forward mutation assay, and the in vivo mouse bone marrow micronucleus assay.
Teratogenicity: In rats, given oral rifapentine during organogenesis at 40 mg/kg/day, there was an increase in resorption rate; litter and mean fetus weight were 20% lower than that of controls. Major malformations were observed including mainly cleft palate and right aortic arch. Minor anomalies or variations at the external, visceral and skeletal examinations were also found increased.
In dams allowed to deliver and rear their pups, a slight decrease in litter size and mean litter weight, an increase in number of stillborn and mortality during lactation were noted at 40 mg/kg/day.
In rabbits, on gestational day 29, litter size and weight were slightly lower at 10 and 40 mg/kg/day, compared to controls. Major malformations were seen in 4 fetuses, one with ovarian agenesis (10 mg/kg/day), one with pes varus (20 mg/kg/day) and 2 fetuses with arhinia, microphthalmia and irregularities of the ossified facial tissues (40 mg/kg/day).
Effect on postnatal development was noted in rats. Pup weights in the 20 mg/kg/day were significantly decreased on post-partum days 1 and 4, which returned to normal on post-partum Day 21.
Following mating of F1 generation pups, slight decreases in litter size, increases in resorption rate, and increases in pre-implantation loss were observed in the offspring of F0 mothers from the 20 mg/kg/day. One abnormal fetus (bilateral, posterior pes varus) was observed in an F1 dam descending from a 20 mg/kg/day F0 rat. (See Use in Pregnancy & Lactation).
Though no specific study on milk excretion was performed in animals, the toxicological data in animals have shown compound-related effects in nursing offspring (i.e., on pups' survival and pups' body weights), while no significant effects were observed in nursing mothers. (See Use in Pregnancy & Lactation.)
Impairment of Fertility: Fertility and reproductive performance were not affected by oral administration of rifapentine to male and female rats at doses of up to 20 mg/kg/day (one-third of the human dose based on body surface area conversions) leading to margin of safety of approximately 7 in terms of AUC.
Microbiology: Antibacterial spectrum: In addition to its activity against most strains of Mycobacterium tuberculosis, rifapentine exhibits in vitro activity against most of the following microorganisms, however, the safety and effectiveness of rifapentine in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms: Staphylococcus aureus (including some strains of methicillin-resistant S. aureus / MRSA); Staphylococcus epidermidis (including some strains of methicillin-resistant S. epidermidis / MRSE).
Other coagulase-negative staphylococci: Aerobic gram-negative microorganisms: Neisseria gonorrhoeae.
Anaerobic microorganisms: Bacteroides fragiles.
"Other" microorganisms: Mycobacterium avium-intracellulare complex.
β-Lactamase production should have no effect on rifapentine activity.
Breakpoints: The following rifapentine Minimum Inhibitor Concentration (MIC) breakpoint (for active Tuberculosis), separating susceptible from resistant M. tuberculosis strains is proposed: susceptible < 0.5 mg/L, resistant > 0.5 mg/L.
This breakpoint has been determined using the Agar Proportion Method in 7H10 or 7H11 agar medium and the Radiometric Proportion Method in liquid 7H12 Middlebrook (12B) medium (using the BACTEC 460 instrument). The rifapentine critical concentration is 0.5 mg/L for both methods.
Susceptibility test results obtained by the two different methods can only be compared if the appropriate antibiotic concentration is used for each test method as indicated above. The use of two quality control strains, H37Rv (ATCC 27294) and H37RvSCC (ATCC 700457) is suggested for both procedures.
Susceptibility of the H37Rv strain (ATCC 27294) should be completely obvious at 0.5 mg/L of rifapentine and resistance of the H37RvSCC strain (ATCC 700457) to the same concentration of rifapentine by the same method should also be completely obvious.
In a recent clinical trial conducted in South Africa, Canada and the United States, radiometric MIC values for susceptible strains of M. tuberculosis were ≤ 0.25 mg/l rifapentine (n = 830), while MIC values for rifamycin-resistant isolates were > 8 mg/L.
Susceptible microorganisms: Susceptible: Mycobacterium tuberculosis.*
Rifapentine shows cross-resistance with rifampicin.
* Clinical efficacy has been demonstrated for susceptible isolates.
Susceptible (based on in vitro data): Staphylococcus species: Bordetella pertussis, Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, Streptococcus pneumoniae, peni-S/I/R.
Not Susceptible (based on in vitro data): Klebsiella pneumoniae, Mycoplasma pneumoniae.
S = Sensitive I = Intermediate R = Resistant β= β-lactamase.
Resistance: Most organisms resistant to other rifamycins are likely to be resistant to rifapentine. In the treatment of tuberculosis, the small number of resistant bacilli present within large populations of susceptible bacilli can rapidly become predominant. In addition, resistance to rifamycin antibiotics has been determined to occur as a single step mutation of the gene that encodes for the beta subunit of the DNA-dependent RNA polymerase. However, other mechanisms of rifamycin resistance observed among certain organisms, such as Nocardia and mycobacteria other than M. tuberculosis cannot be ruled out. Appropriate susceptibility tests should be performed in the event of persistently positive cultures.
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