Rifapentine – A New Edge to Tuberculosis Therapy

Tuberculosis (TB) is a major infectious disease caused by the bacterium Mycobacterium tuberculosis. Current estimates suggest that one third of the world’s population is infected with TB, resulting in 2 million deaths per year^{1- 2}. TB is considered as global epidemic and current statistics shows that, between 2002 and 2020, nearly 1000 million people around globe will be newly infected, over 150 million people will get sick, and 36 million will die of TB, if this dreaded disease is not controlled. Of the 2 million deaths caused by TB annually, 98 per cent occurs in developing countries.

Multi-drug-resistant tuberculosis (MDRTB) is one of the key problems associated with treatment of TB³. Emergence of the Human Immuno-deficiency Virus (HIV) and Acquired Immuno Deficiency Syndrome (AIDS) has contributed to a significant increase in the worldwide incidence of TB⁴. Worldwide, TB is the most common cause of death among patients with AIDS, killing 1 of every 3 patients⁵. This has made the therapy of either disease much tougher for patients suffering with these diseases. Phased classical therapy of the TB consisting of Rifampicin (RMP), Isoniazide (INH), Pyrazinamide (PYZ) and Ethambutol (ETH) is been practiced for five decades. New drug discovery in the treatment of TB has been a issue of debate. Due to low return on investment, very few new drugs have been introduced in the last 30 years by the pharmaceutical companies⁶. Now, efforts are being made for identification of new therapeutic targets and lead molecules for treatment of TB or approach of improved drug delivery techniques of the presently available anti-TB drugs.

Rifapentine (RPT) is a new semi-synthetic rifamycin analogue belonging to the class of piperazinyl hydrazone derivatives of 3-formyl rifamycin⁷. Anti-microbial spectrum of RPT (figure 1) particularly against Mycobacterium tuberculosis is similar to RMP⁸. United States Food and Drug Administration (USFDA) has approved RPT for the treatment of pulmonary tuberculosis⁹. RPT has become choice of drug over RMP, as dosage regimen of RPT is only twice weekly for initial treatment of TB and once weekly during the continuation phase of the treatment with the virtue of its longer half life¹⁰.

Regulatory aspects of RPT:

USFDA has granted accelerated approval for RPT for the treatment of pulmonary TB in June 1998, making it the first drug approval for this indication in last 25 years for use in United States. It is first drug discovery in the area of Anti-TB drugs, since 1967 when RMP was firstly introduced in the treatment of TB. RPT is marketed alone for pulmonary TB as well as also used in combination with other anti-TB agents.

Hoechst Marion Roussell of Kansas City, Missouri, (Now known as Aventis Pharmaceuticals) holds the patent (Aventis NDA 21-024/SE7-005 10/20/00 12/11/01) [11] for RPT and is marketed under the trade name PRIFTIN^®. The prevalence of pulmonary TB in United States is lower as compared to other infectious diseases and thus RPT has been designated as an orphan drug. Orphan drug status guarantees the developer seven years of market exclusivity for the orphan drug indication following FDA's marketing approval, and provides other financial incentives for drug development.

Physicochemical drug profile of RPT:

RPT [3-[N-(4-Cyclopentyl-1-piperazinyl) formimidoyl] rifamycin] semi-synthetic rifamycin derivative, bearing molecular formula - C47H64N4O12, is reddish brown crystalline powder. The molecular weight of RPT (CAS No: 61379-65-5) is 877.04 and is amphoteric in nature. It has melting point of 172 °C and 1 % suspension of the drug gives pH of 6 ¹¹. European patent literature on RPT shows it is a mixture of the different solid polymorphic forms. It has been reported that, it is a blend of crystalline and amorphous forms, which ultimately determines its solubility and bioavailability in in-vivo studies¹². The predominance of the polymorphic form in the bulk of the RPT depends on the type of re-crystallization solvent used. Our laboratory findings suggests that, RPT is poorly soluble in water¹³, has moderate solubility in methanol, ethanol and is highly soluble in acetonitrile and chloroform. RPT shows pH dependent solubility, solubility increases with increase in the pH from 1 to 9. It shows maximum solubility at pH 9 both in buffered and un-buffered pH solutions. Like RMP, RPT also shows high degradation rate acidic medium (pH of 1 & 2) both in buffered and un-buffered solutions. It shows maximum stability at pH 5 in buffered pH solution and at pH 6 & 7 in un-buffered pH solutions. Because of its greater solubility, stability at higher pH (pH 6-9) values and amphoteric nature, it is well absorbed through out gastro-intestinal tract and more predominantly from small intestine. RPT is highly lipophilic with Calc. Log P (KowWin method) value^14-15 of 2.98; however, our laboratory study for log P by classical water-octanol method produced value of 2.254.

Analytical and bioanalytical methods for analysis of RPT:

No pharmacopoeias have reported any analytical method for estimation of RPT in bulk, dosage form or in biological matrices as RPT is yet to be included in pharmacopoeias. Our groups has, however reported two simple UV spectroscopic methods for the estimation of the RPT in bulk as well as in pharmaceutical formulations¹⁶ as no other such methods were available.

Three HPLC methods^17-19 and a microbiological assay²⁰ have been reported for estimation of RPT in various biological matrices. He et al has reported HPLC method in human serum involving use of RMP as internal standard. Method involved complex extraction procedures with limit of quantitation of 500 ng/ml¹⁷. The HPLC method reported by Riva et al for estimation of RPT in human plasma involved use of shielded hydrophobic phase column. Nevertheless, method has limit of detection of 200 ng/ml¹⁸. Lee et al reported a method in dog serum based on column switching technique with limit of detection of 100 ng/ml¹⁹. The total run time of the method was up to 25 minutes, making the method time consuming. Kenny et al. has reported a microbial assay of RPT but the method was found to over estimate the drug concentration due to presence of active metabolite – 25-desacetyl rifapentine formed from the RPT²⁰.

Pharmacological profile:

RPT inhibits DNA-dependent RNA polymerase present in susceptible strains of Mycobacterium tuberculosis but not in mammalian cells²¹. RPT is active against all the species of Mycobacterium tuberculosis complex (MAC) ²². At therapeutic levels, RPT exhibits bactericidal activity against both intracellular and extracellular organisms. In the early studies, RPT has been reported to have an in vitro activity the same as or higher than that of RMP^23-24. Subsequent studies have shown that the broth-determined Minimum Inhibitory Concentration of RPT was two to threefold lower than those of RMP ²⁵.

RPT has been reported effective (in vitro and in vivo) against the protozoan parasite Toxoplasma gondii. RPT inhibited the intracellular replication of parasites and was not cytotoxic for the host cells at inhibitory concentrations²⁶. Recently, RPT also has been indicated in treatment of Mycobacterium Kansasii²⁷. Mycobacterium kansasii is second to MAC as a cause of serious non-tuberculous mycobacterial infection in patients with AIDS ^28-29.

Pharmacokinetic profile of RPT:

Pharmacokinetics of RPT in animals:

Pharmacokinetics of RPT has been reported in the rat, the mouse, the rabbit and the monkey. It has shown characteristic and variable pharmacokinetic profiles in common laboratory animals. In the rats, oral absorption of RPT appears to be dose-dependent but with a satisfactory oral absorption (84%) after a dose of 3 mg/kg and 65% after 10 mg/kg³⁰. RPT undergoes rapid liver uptake and it diffuses into the tissue compartment more slowly, with particular affinity for the adrenals, pancreas and kidneys. It has been observed that concentrations higher than in plasma were also measured in the lungs. Elimination of RPT from the blood and tissue compartments suggests a non linear capacity-limited kinetics where the terminal elimination phase has monoexponential course³⁰. Terminal plasma half-life of RPT ranged between 14 and 18 hours and is eliminated mainly via the bile with the feces (92% of dose). In mice and monkeys RPT showed a kinetic profile resembling that obtained in rats, whereas in rabbits is metabolized and/or eliminated much more rapidly with a half-life of only 1.8 hours^30-31. The clearance of the RPT was also found higher in rabbit (197.9 ml/kg×hr) as compared to that in rat (33.6 ml/kg×hr) and mice (52.7 ml/kg×hr). The calculated distribution volume (V/F) of RPT in rabbit was found to be lowest among all the species (V/F rabbit = 0.44 liter/kg, V/F rat = 0.95 liter/kg, V/F mice = 1.29 liter/kg). Over all AUC values for unaltered RPT were lower in rabbit than those calculated for rat and mice³⁰. RPT shows poor bioavailability in rabbit, which may be attributed to its high metabolism or biotransformation rate and clearance.

Pharmacokinetics of RPT in humans:

RPT although amphoteric in nature, exhibits acidic nature (pH of 1% solution of RPT is 6) and is highly lipophilic in nature. It gets predominantly absorbed from small intestine and other parts of the colon. The maximum concentrations (C_max) of 12 – 15 µg/ml were achieved in 5 to 6 hours (T_max) after administration of the 600 mg RPT³². Compared with an oral solution, the relative bioavailability of RPT is 70% following oral administration of tablets³³. RPT is 95% protein bound³⁴. RPT gets metabolized by CYP3A4 enzyme family in liver to a major active metabolite – 25-desacetyl rifapentine. The other minor metabolites reported are 3-formyl RPT and 3-formyl-25-desacetyl rifapentine³⁵.

Similar to 25-desacetyl metabolites of RMP and rifabutin, the 25-desacetyl metabolite of RPT has in vitro activity against Mycobacterium tuberculosis^36-37. RPT showed half life of 13 hours in humans³⁸. During the multiple dose therapy, RPT has been reported to induce CYP3A4 enyzyme³⁹ but inductive potential of the RPT was observed less as compared to the RMP⁴⁰. In an open-label investigation, pharmacokinetics of RPT and its active metabolite, 25-desacetyl rifapentine, has been characterized in patients with varying degrees of hepatic dysfunction. Maximum plasma concentration of RPT were found to be lower, time to maximum plasma concentration (T_max) was greater, and elimination half-life (t_1/2) was longer in the patients with moderate-to-severe hepatic dysfunction than in those with mild-to-moderate dysfunction. However, mean area under the concentration-time curve extrapolated to infinity (AUC 0-∞) was found similar to that of the normal patients without hepatic impairment ⁴¹. AUC (0-∞) values in patients with hepatic dysfunction were 19% to 25% higher than values previously reported for healthy volunteers. Study concluded that RPT is well tolerated in hepatic dysfunction patients, irrespective of the etiology or severity of hepatic dysfunction. The results suggest that no adjustments for dosage for RPT are needed in such patients⁴¹.

Single-dose pharmacokinetics of RPT in women revealed that, there is no significant difference in pharmacokinetics of RPT in males and females, except discoloration of the urine was reported in female subjects ⁴².

Pharmacokinetic studies performed in elderly patients revealed that no age-related changes in the pharmacokinetic profile of RPT were found and is unlikely to be associated with toxicity. No dose adjustment for this antibiotic is recommended in elderly patients⁴³. Pharmacokinetics of RPT has been reported in adolescents, which appears to be similar as that of in adult population⁴⁴. Consecutive-dose pharmacokinetics of RPT in patients diagnosed with pulmonary TB has been studied at doses of 600, 750 and 900 mg/day. The drug was administered for five consecutive days and showed that variability observed between individuals and between occasions was small and similar to that was observed in healthy volunteers⁴⁵.

The pharmacokinetics of RPT has 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 RPT and its 25-desacetyl metabolite is not known.

Clinical studies with RPT:

To establish the clinical efficacy and safety of the RPT, many clinical studies have been carried out so as to assess the effectiveness of RPT dosage regimen to be used alone and also with other anti-TB agents.

In an initial efficacy trial of RPT conducted in China, 560 patients with culture-confirmed pulmonary TB (486 patients with initial episodes of TB and 74 re-treatment cases) were randomized to receive various regimens consisting of the INH, ETH, PYZ, and RPT. Five hundred eleven patients complied to TB therapy in this trial. More than 99% of patients undergoing initial TB treatment and 94% of re-treatment cases had negative cultures for Mycobacterium tuberculosis at the end of clinical trial, irrespective of the treatment regimen used⁴⁶. One of the earliest reports on the clinical studies of RPT was reported by He G.J. ⁴⁷. A clinical study about the efficacy of RPT in the treatment of TB and 3 years follow up on initial pulmonary TB patients ( n=267) concluded that the twice-weekly of RPT has at least an effect similar to RMP given daily.

Table 1 summarizes the list of clinical trials of RPT and other drugs combinations in TB treatment. It could be assessed from the table that, extensive studies have been carried out for clinical use of RPT in various dosage regimens. Table 2 summarizes the current clinical trials undergoing for RPT for the use in the continuous phase of the TB treatment.

RPT resistance:

Drug resistance is one of the major problems in the TB treatment. Multi drug-resistant tuberculosis (MDR-TB) has emerged as a major threat to TB control, especially in Asian countries⁵³. The number of cases resistant to treatment by anti-TB drugs has increased at the same time the incidence of TB has also risen⁵³. A major contributor to drug resistance is the failure of patients to complete their drug treatment (non-compliance) ⁵⁴.

In the classical treatment of TB, patients needed to take medication (RMP + INH + ETH + PYZ) daily for two months followed by twice weekly doses (RMP + INH) for four months. To improve the patient compliance, Directly observed therapy (DOT) programs have been implemented and it proved to be successful to some extent in terms of patient compliance ⁵⁵. DOT patients receive their medications directly under the supervision of a healthcare professional.

RPT has an initial two-month dosing schedule of twice weekly, administered with daily INH, PYZ and ETH similar to past regimens, but in the second course of therapy, patient’s dosing schedule is once weekly (RPT + INH) rather than twice weekly (RMP + INH)⁵⁶. Hence, due to reduced frequency of drug administration, patient compliance with therapy is expected not only to increase the rate at which patients are cured of TB but also reduce development of drug resistance. Moreover, RPT has been reported to be effective against RMP-sensitive and RMP-resistant strains of Mycobacterium tuberculosis and against the Mycobacterium avium / intracellulare / scrofulaceum (MAIS) complex ⁵⁷.

Anti-TB drug resistance is suspected mainly due to single point mutations occurring in the b subunit of the gene (rpo b) coding for DNA-dependent RNA polymerase⁵⁸. In a mechanism based study for resistance, impact of specific rpoB mutant alleles on the development of rifamycin resistance has bee reported. Mutations were incorporated into the rpoB gene of Mycobacterium tuberculosis H37Rv, contained on a mycobacterial shuttle plasmid, by in vitro mutagenesis. Recombinant Mycobacterium tuberculosis clones containing plasmids with specific mutations in either codon 531 or 526 of rpoB exhibited high-level resistance to all rifamycins, whereas clones containing a plasmid with a mutation in codon 516 exhibited high-level resistance to RMP and RPT⁵⁹. Thus on molecular basis, RPT shows complete cross-resistance with RMP. Very first report of such a resistance has been reported in patients with HIV-related TB, treated with once-weekly RPT and INH ⁵⁰.

Activity of RPT and its metabolite 25-desacetyl rifapentine was compared with RMP and rifabutin in Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis and Mycobacterium bovis BCG, where it has been reported that clinical isolates of Mycobacterium tuberculosis with a high degree of resistance to RMP were also highly resistant to rifabutin and RPT⁶⁰.

From available literature on RPT resistance, it can be seen that RPT demonstrate the cross resistance as that of RMP, but because of stronger bactericidal potency of RPT as compared to RMP, some RMP resistant strains still show susceptibility to RPT, which suggests that RPT, can be still effective in the treatment of RMP resistant TB ⁶¹.

Adverse effects of RPT:

Adverse effects or side effects of RPT are comparable to those of RMP such as darkened urine, yellowing of the eyes or skin⁶². The investigators in the TB treatment clinical trial (Study 008) assessed the causality of adverse events with RPT and RPT with other anti-TB drugs as compared to RMP or RMP with other anti-TB drugs in intensive as well as continuation phase of TB treatment. Hyperuricemia was the most frequently reported adverse effect but it was assessed as treatment related and was most likely related to the PYZ, since no cases were reported in the continuation phase with RPT when this drug (PYZ) was no longer included in the treatment regimen with RPT.

Elevated Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) levels and neutropenia were the most common treatment-related adverse events reported in patients receiving RPT indicating the risk of hepato-toxicity ⁶³. Among other adverse effects, RPT can cause thrombocytopenia with the signs/symptoms of easy bruising and/or slow blood clotting and gastrointestinal intolerance with the sign/symptom of upset stomach⁶⁴.

RPT is contraindicated in patients hypersensitive to RMP or rifabutin and has shown some incidence of proteinuria, pyuria, and lymphopenia in some patients⁶⁵. Other adverse effects associated with RPT treatment are urticaria, skin discoloration, thrombocytopenia, neutrophilia, puerperal, hematoma, hyperkalemia, hypovolemia, increased LDH, esophagitis, gastritis, pancreatitis. Rifapentine is not recommended as a substitute for RMP because its safety and effectives have not been established for the treatment of patients with HIV related TB ⁶⁶.

Clinically important drug interactions of RPT:

Metabolism related:

Like RMP, RPT is also an inducer of cytochrome enzymes CYP3A4 and CYP2C8/9 in long term therapy ⁶⁷. Therefore, RPT may increase the metabolism of other co-administered drugs that are metabolized by these enzymes. The magnitude of enzyme induction by RPT is dose and dosing frequency dependent. In vitro and in vivo enzyme induction studies have suggested RPT enzyme induction potential may be less than RMP but more potent than rifabutin⁴⁰.

RMP has been reported to accelerate the metabolism and may reduce the activity of the drugs like repaglinide⁶⁸, glyburide & glipizide⁶⁹, praziquantel⁷⁰ oral contraceptives ⁷¹, ropivacaine⁷², trimethoprim & sulfamethoxazole⁷³, diazepam⁷⁴, delavirdine⁷⁵, simvastatin ⁷⁶, amprenavir⁷⁷, zidovudine⁷⁸, ondansetron⁷⁹, amiodarone⁸⁰ etc.; hence, RPT may also increase the metabolism and decrease the activity of these drugs. Dosage adjustments of the above drugs or of drugs metabolized by cytochrome CYP3A4 or CYP2C8/9 may be necessary if they are given concurrently with RPT.

The most significant drug interaction with RPT was observed with indinavir. The maximum concentration (C_max) and AUC of indinavir are reduced by 55% and 70%, respectively, when RPT is co-administered with indinavir³³.

Many drug-drug interactions of the RPT are not clinically proved. Secondly, wide use of this drug in variety of patients with wide range of the concurrent drugs will further provide more information on the potential drug-drug interaction in future.

Carcinogenesis, impairment of fertility with RPT:

As per the leaflet of the prescribing information (final printed labeling (FPL) / package insert) on PRIFTIN^®, carcinogenicity studies with RPT have not been completed. RPT was found negative in the various genotoxicity tests like in vitro gene routation 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/hypoxanthine-guanine-phosphoribosyl transferase, forward mutation assay: in vitro chromosomal aberration assay utilizing rat lymphocytes; and in vivo mouse bone marrow mocronucleus assay. Fertility and reproductive performance were not affected by oral administration of RPT to male and female rats at doses of up to one-third of the human dose (based on body surface area conversions) ⁸¹.

Teratogenic effects of RPT:

RPT has shown teratogenic effects in studies carried out with rats and rabbits. It has shown major malformations including ovarian agenesis, pes-varus, arhinia, microphthalmia⁸¹.

Laboratory Tests to be undertaken during RPT treatment:

Patients treated for TB with RPT should undergo baseline measurements of hepatic enzymes, bilirubin, a complete blood count, and a platelet count (or estimate) before and during RPT treatment. Patient should be assessed at least once in month during RPT therapy and should be specifically questioned concerning symptoms associated with various adverse reactions. All patients with abnormalities indicated in laboratory testing should consult physician before further treatment with RPT. Therapeutic concentrations of RMP have been shown to inhibit standard microbiological assays for serum folate and Vitamin B12. Similar drug-laboratory interactions should be considered for RPT and thus alternative assay methods should be considered⁸¹.

Dosage form:

RPT is available as tablet formulation (PRIFTIN ® , Aventis Pharmaceuticals) of strength 150 mg. The 150 mg tablet contains inactive ingredients such as calcium stearate, disodium EDTA, FD&C Blue No: 2 aluminium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, propylene glycol, sodium ascorbate, sodium laury sulfate, sodium starch glycolate, synthetic red iron oxide, and titanium dioxide. PRIFTIN (RPT) 150 mg tablets are supplied as pink film coated tablets packaged in aluminum foil blisters to be stored at Store at 25° C (77° F) ¹¹.

Dosage and administration:

RPT should not be used alone, in initial treatment or in re-treatment of pulmonary TB. In the intensive phase of short-course therapy for 2 months, 600mg (four 150mg tablets) of RPT should be given twice weekly with an interval of not less than 3 days (72 hours) between doses³³. For those patients with tendency of nausea, vomiting or gastrointestinal upset, administration of RPT with food may be useful.

In the intensive Phase of TB treatment, RPT must be administered in combination with other anti-TB drugs like INH, PYZ, ETH, or streptomycin. The Advisory Council for the Elimination of Tuberculosis⁸², the American Thoracic Society and the Centers for disease Control⁸³ and Prevention also suggest that either streptomycin or ethambutol can be added to the treatment unless the probability of INH resistance is very low⁸². Following the intensive phase, during the continuation phase of treatment, RPT should be given once weekly for 4 months in combination with INH or an appropriate agent for susceptible organisms^{33, 83}.

Conclusions:

Mycobacterial infection is still a challenge for all the medical and pharmacy fraternity. The therapy of TB is different than other bacterial infections in number of aspects. Mycobacteria are not susceptible to many classes of antibacterial agents. As a result, mycobacterial infections often require treatment with drugs that are not commonly used for infections with other bacteria and often have small therapeutic windows.

Tubercle bacilli are generally slow to respond to antimicrobial agents and have shown high prevalence of the resistance to various Anti-TB drugs thus therapy must be given with multiple drugs for prolonged periods of time. The major concern for the design of newer anti0tubercular drugs remains with novel pharmacokinetics and Pharmacodynamic properties. This has always prompted scientists to develop novel therapeutic agents with high potency and low toxicity with broad spectrum of activities. RPT is one of the successful agents which is discovered in recent past for the treatment of TB.

RPT is an attractive drug for use in treatment of TB due to its long half-life, suitability for intermittent dosing, and the most importantly that it is mycobactericidal. From the literature as well as clinical evidences, RPT is a significant promise as a new therapeutic agent in the treatment of active TB. It has also been suggested that once weekly administration of RPT may also be useful in preventive therapy in persons with ‘latent Mycobacterium tuberculosis infection’. RPT’s efficacy at the currently approved dosage of 600 mg per week may be equal or slightly lower than that of RMP. Further clinical studies are needed to determine if equal or greater efficacy can be achieved with higher doses of RPT. Research in direction of dose and dosing intervals optimization is needed, before RPT can be safely substituted for other well established drugs in the routine therapy of TB.

An important aspect of the anti-TB therapy is pharmacoeconomics of treatment, which is especially important for developing country like India. One of the important reasons for the patient non-compliance for anti-TB treatment is cost of the therapy. Currently RMP is less expensive than RPT. Further pharmacoeconomic studies in terms of cost effectiveness analysis, cost-benefit analysis along with cost minimization analysis are needed to evaluate costs of treatment in TB treatment or cost of relapse treatment and treatment failure in patients receiving these agents.

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Figure 1:

 

Table 1:

List of clinical studies of RPT and other drugs combinations in TB treatment

Title	Type / study details	Location	Outcome	Ref.
Tolerability of RPT 600, 900, and 1,200 mg Plus INH in the Continuation Phase of TB Treatment	A multi-center, Phase II, prospective, randomized, double-blind study of the tolerability and safety of three doses of RPT (600, 900, and 1,200 mg) given with INH 15 mg/kg once weekly in the continuation phase of TB treatment.	USA & Canada	RPT 900-mg, once-weekly dosing appears to be safe and well tolerated	[48]
RPT and INH in the Continuation Phase of Treating Pulmonary Tuberculosis	A randomized comparison has been made of three times weekly rifampicin plus INH with RPT plus INH given once weekly or on 2 of 3 wk in the continuation phase of 6-month regimens for the treatment of pulmonary TB in 672 Chinese patients	Hong Kong	The high relapse rate in the regimen suggests that the RPT dose should be increased	[49]
Acquired rifamycin mono-resistance in patients with HIV-related tuberculosis treated with once-weekly RPT and INH.	Study compared a once-weekly regimen of INH and RPT with twice weekly INH and rifampicin in the continuation phase (the last 4 months) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients.	USA	Relapse occurred among HIV-seropositive tuberculosis patients treated with once-weekly INH /RPT continuation-phase regimen	[50]
Pharmacokinetics of RPT in subjects seropositive for HIV	Phase I clinical trail to characterize the single-dose pharmacokinetics of RPT and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with (HIV)	USA	No dosage adjustments may be required for RPT in HIV-infected patients undergoing treatment for TB.	[51]
RPT and INH once a week versus rifampicin and INH twice a week for treatment of pulmonary TB in HIV-negative patients	Randomized clinical trail, treatment with either 600 mg RPT plus 900 mg INH once a week or 600 mg rifampicin plus 900 mg INH twice a week to HIV-negative people with drug-susceptible pulmonary TB	USA & Canada	RPT once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography	[52]

Table 2:

Currently undergoing clinical trial of RPT in TB treatment

Title	Purpose	Sponsor /Investigator	Location*
A Study of the Effectiveness and Tolerability of Weekly RPT /INH for Three Months Versus Daily INH for Nine Months for the Treatment of Latent TB Infection	The primary objective of this open-label Phase III clinical trial is to compare the effectiveness of a three-month (12-doses) regimen of weekly RPT (900mg) and INH (15 mg/kg) to the effectiveness of a nine-month (270-doses) regimen of daily INH (5 mg/kg).	Centers for Disease Control and Prevention Department of Veterans Affairs	Multi-centre Research and Evaluation Branch , Division of TB Elimination, USA

* Retrieved from http://www.hivnet.ubc.ca/e/clinicaltrials/N007.html & http://www.clinicaltrials.gov/show/NCT00023452

 

 

 

Dr. R.N. Saha * is professor of Pharmacy
and Dean, Faculty Division III and Educational Development Division, BITS,
Pilani. He obtained his B.Pharm and M.Pharm degrees from Jadavpur University,
Kolkata and Ph.D from BITS, Pilani. He has more than 25 years of teaching and
research experience and guided several doctoral students, M.Pharm & B.Pharm
students. He has many publications in international and national journals and
presented several papers in international and national conferences in India
and abroad. He has successfully completed several government and industry sponsored
projects and continuing so. Dr. Saha has developed commercial products for industries
and transferred technologies for production to industries. He is expert member
to various committees of UGC and other agencies and selection committees of
CSIR laboratories and several universities / colleges. He is also member of
Board of Studies of several universities / colleges and visiting professor to
few universities.

Contact address:

Dr.R.N.Saha, Professor of Pharmacy, Dean, FD III & Educational Development
Division, Pharmacy Group, Birla Institute of Technology and Science, Pilani
-333031, Rajasthan, India. Email: rnsaha@bits-pilani.ac.in, Phone: 091-1596-245074-ext-284
, Fax: 091-1596-244183.

* Author for correspondence

Mr. Kole P.L. is a faculty at Pharmacy
Group, BITS, Pilani. He has obtained his B. Pharm and M.Pharm degrees from
Shivaji University, Kolhapur, Maharashtra. He secured second rank in B.Pharm
and first rank in M.Pharm in merit list of Shivaji University. Currently he
is pursuing his doctoral degree from BITS, Pilani, under the guidance of Dr.
R.N.Saha. Mr. Kole P.L. has five years of teaching and research experience.
Along with academics, he also has been investigator in the various governmental
and industry sponsored projects as part of team member of Dr. R. N. Saha. He
has presented several papers in various conferences and symposiums of international
and national repute. He has guided many B.Pharm and M.Pharm students on various
study oriented and laboratory oriented projects. He also is life member of various
societies like APTI, FIP, ISSST, IPS SPI etc.

Contact info:

Kole P.L, Lecturer, Pharmacy Group, FD III, Birla Institute of Technology and
Science, Pilani -333031, Rajasthan, India. Email: plkole@bits-pilani.ac.in Phone:
091-1596-245074-ext-458 Fax: 091-1596-244183