Rifapentine

MIC: 0.015 - 0.06 mg/ml

Tuberculosis is a widespread, infectious disease caused by various mycobacteria strains, usually Mycobacterium tuberculosis. Tuberculosis typically attacks the lungs, but can also affect other parts of the body. Rifapentine is an antibiotic drug used in the treatment of tuberculosis.

In vitro: The activities of rifampin and rifapentine against Mycobacterium tuberculosis residing in human monocytederived macrophages were determined. The MIC and MBC of rifapentine for intracellular bacteria were two- to four-fold lower than those of rifampin. For extracellular bacteria, this difference was less noticeable. [1].

In vivo: Once-a-week exposure to rifapentine concentrations equivalent to that attained in blood after one 600-mg dose resulted during the first week in a dramatic decline in the number of bacteria, and such decline was maintained at a minimal level for a period of four weeks. The prolonged effect of rifapentine found may be associated with high ratios of intracellular accumulation, which were four- to fivefold higher than those found for rifampin [1].

Clinical trial: Rifapentine can be administered twice weekly during the intensive phase of tuberculosis treatment and then once weekly during the continuation phase of treatment. Its efficacy at the approved dosage of 600 mg may be slightly lower than that of rifampin. Studies are needed to determine if equal or greater efficacy could be achieved with higher doses of rifapentine [2].

Reference:
[1] Mor N, Simon B, Mezo N, Heifets L.  Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages. Antimicrob Agents Chemother. 1995 Sep;39(9):2073-7.
[2] Temple ME, Nahata MC.  Rifapentine: its role in the treatment of tuberculosis. Ann Pharmacother. 1999 Nov;33(11):1203-10.

Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials.[Pubmed:28124478]

Clin Pharmacol Ther. 2017 Aug;102(2):321-331.

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare Rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with Rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high Rifapentine doses.

Drug Release Characteristics and Tissue Distribution of Rifapentine Polylactic Acid Sustained-Release Microspheres in Rabbits after Paravertebral Implantation.[Pubmed:28210500]

Iran Red Crescent Med J. 2016 Aug 13;18(11):e38661.

BACKGROUND: Rates of drug-resistant tuberculosis (TB) and TB associated with human immunodeficiency virus (HIV) infection have increased dramatically, intensifying challenges in TB control. New formulations of TB treatment drugs that control drug release and increase local drug concentrations will have a significant impact on mitigating the toxic side effects and increasing the clinical efficacy of anti-TB drugs. OBJECTIVES: The aim was to observe the sustained release characteristics of Rifapentine polylactic acid sustained-release microspheres in vivo and the accumulation of Rifapentine in other tissues following paravertebral implantation. METHODS: This study is a basic animal experimental study that began on July 17, 2014 in the Fifth Affiliated hospital of Xinjiang Medical University. One hundred and eight New Zealand white rabbits (weighing 2.8 - 3.0 kg, male and female, China) were randomly divided into three groups of 36 rabbits each. Blood and tissue samples from the liver, lungs, kidneys, vertebrae, and paravertebral muscle were collected at different time points post-surgery. High performance liquid chromatography (HPLC) analysis with a biological internal standard was used to determine the drug concentrations in samples. RESULTS: In group A, no significant differences in Rifapentine concentrations in the liver were detected between any two time points (P > 0.05). However, the differences in Rifapentine concentrations between day 10 and day 21 were statistically significant (P < 0.05); for days 21, 35, 46, and 60, the differences in Rifapentine concentrations between two sequential time points were not statistically significant (P > 0.05). In group B, the differences in Rifapentine concentration between days 3 and 10 in vertebral bone and in paravertebral muscles were statistically significant (P < 0.05). Rifapentine was detected in the vertebral bone tissue in the group C animals. The Rifapentine concentrations between two sequential time points were statistically significant (P < 0.05). Rifapentine could not be detected in the paravertebral muscles 46 days after the operation. The differences in Rifapentine concentrations between two sequential time points among days 3, 10, 21, and 35 were statistically significant (P < 0.05). CONCLUSIONS: After paravertebral implantation of Rifapentine polylactic acid sustained-release microspheres, the concentration of Rifapentine in local vertebral bone tissues was maintained above the TB minimum inhibitory concentration for up to 60 days with no apparent accumulation of the drug in other tissues.

Treatment completion for latent tuberculosis infection: a retrospective cohort study comparing 9 months of isoniazid, 4 months of rifampin and 3 months of isoniazid and rifapentine.[Pubmed:28196479]

BMC Infect Dis. 2017 Feb 14;17(1):146.

BACKGROUND: The U.S. Centers for Disease Control and Prevention (CDC) recommended a new regimen for treatment of latent tuberculosis (three months of weekly isoniazid and Rifapentine) in late 2011. While completion rates of this regimen were reported to be higher than nine months of isoniazid, little is known about the completion rates of three months of isoniazid and Rifapentine compared to nine months of isoniazid or four months of rifampin in actual use scenarios. METHODS: We conducted a retrospective cohort study comparing treatment completion for latent tuberculosis (TB) infection in patients treated with nine months of isoniazid, three months of isoniazid and Rifapentine or four months of rifampin in outpatient clinics and a public health TB clinic in Seattle, Washington. The primary outcome of treatment completion was defined as 270 doses of isoniazid within 12 months, 120 doses of rifampin within six months and 12 doses of isoniazid and Rifapentine within four months. RESULTS: Three hundred ninety-three patients were included in the study. Patients were equally likely to complete three months of weekly isoniazid and Rifapentine or four months of rifampin (85% completion rate of both regimens), as compared to 52% in the nine months of isoniazid group (p < 0.001). These associations remained statistically significant even after adjusting for clinic location and type of monitoring. Monitoring type (weekly versus monthly versus less often than monthly) had less impact on treatment completion than the type of treatment offered. CONCLUSIONS: Patients were equally as likely to complete the three months of isoniazid and Rifapentine as four months of rifampin. Four months of rifampin is similar in efficacy compared to placebo as isoniazid and Rifapentine but does not require directly observed therapy (DOT), and is less expensive compared to combination therapy with isoniazid and Rifapentine, and thus can be the optimal treatment regimen to achieve the maximal efficacy in a community setting.

Three months of weekly rifapentine plus isoniazid for latent tuberculosis treatment in solid organ transplant candidates.[Pubmed:28276008]

Infection. 2017 Jun;45(3):335-339.

BACKGROUND: Isoniazid daily for 9 months is the recommended regimen for latent tuberculosis infection (LTBI) in solid organ transplant (SOT) candidates, but its use is controversial, due to reports of hepatotoxicity and low treatment completion rates. A 12-week course of once weekly directly observed therapy (DOT) with isoniazid plus Rifapentine (3HP) is a new LTBI treatment regimen. Tolerability and safety data of 3HP LTBI treatment in SOT candidates are limited. METHODS: Twelve consecutive SOT candidates who underwent DOT with 3HP for LTBI at Westchester Medical Center, Valhalla, New York, USA, between January 2013 and August 2016 were prospectively evaluated for tolerability and safety of 3HP. The diagnosis of LTBI was made in a person with a positive interferon-gamma release test, without a history of previously treated active or latent tuberculosis infection, and without signs, symptoms, or radiographic evidence of active tuberculosis. Patients were followed up 1 month after treatment completion and at routine follow-up visits with their transplant providers. RESULTS: Eleven patients were men, and the median age was 60 years (range 44-72). Eight patients were liver, and four kidney transplant candidates. The median Model for End-Stage Liver Disease (MELD score) was 17 (range 10-31). All patients completed treatment. Only a single patient developed transaminitis greater than twice the baseline value. Three patients underwent liver transplantation. None of them developed tuberculosis at 9, 22, or 40 months following transplantation. CONCLUSION: Directly observed 3HP LTBI treatment was not associated with hepatotoxicity, even in patients with higher MELD scores. Further studies are needed to confirm the safety and efficacy of this LTBI treatment regimen in the SOT population.