Chapter 86 Newer Anti-TB Drugs and Drug Delivery Systems

Alladi Mohan, D Prabath Kumar, J Harikrishna

INTRODUCTION TABLE 1 │ Currently used antituberculosis drugs Tuberculosis (TB) has been a leading cause of death since time Essential first-line antituberculosis drugs immemorial and it continues to cause immense human misery even today. As per the currently available Global Tuberculosis Control Isoniazid 1 Rifampicin Report 2012 of the World Health Organization (WHO) in the year Ethambutol 2011, there were 8.7 million incident cases of TB and 1.4 million Pyrazinamide deaths. Effective predictable treatment of TB became available only in the mid-1940s with the introduction of streptomycin. In Second-line parenteral agent (injectable antituberculosis drugs) the late 1970s, TB appeared to be fading away from being a major public health problem at least in the developed countries. The Kanamycin human immunodeficiency virus (HIV) infection and acquired Capreomycin immunodeficiency syndrome (AIDS) pandemic in the early 1980s resulted in a global resurgence of TB.2 The recent years have also Fluoroquinolones witnessed the emergence and global presence of multidrug-resistant Ciprofloxacin TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) that are Ofloxacin highly lethal, extremely expensive and complicated to treat have Levofloxacin been causing concern worldwide.3 Moxifloxacin A major paradigm shift in the treatment of TB occurred with Gatifloxacin the introduction of rifampicin, the last landmark drug introduced Oral bacteriostatic second-line antituberculosis drugs 4 for TB treatment. Based on the data from studies conducted in the Ethionamide 1970s, the standard treatment duration of anti-TB treatment could be Prothionamide shortened to 9 months. Rediscovery of pyrazinamide and combining Cycloserine it in a reduced dosage to rifampicin-containing regimens facilitated Terizidone the emergence of currently used short-course treatment regimens.5-9 p-aminosalicylic acid 3,10,11 The currently used anti-TB drugs have been listed inTable 1. Other drugs In spite of being a global public health problem, TB has remained Clofazimine a neglected disease. Since the introduction of rifampicin, anti- TB drug discovery has been sluggish. Since then, no new drug has Amoxycillin-clavulanate become available that can be compared to rifampicin in terms of utility and safety. In the era of M/XDR-TB, there is an urgent need for new anti-TB drugs that are more effective and have less toxicity. Imipenem There is also a need for newer and innovative anti-TB drug delivery Thioridazone systems. In this review, we have attempted to summarize evidence Source: References 3,10,11 regarding the efficacy and potential of repurposed existing anti-TB drugs and emerging new anti-TB drug molecules in the treatment of active TB disease. drugs (Table 2).12 Some of the potentially useful anti-TB drugs beyond preclinical development have been discussed in this chapter. ANTITUBERCULOSIS DRUG PIPELINE The current concepts and processes of drug discovery and devel- Repurposed Existing Antituberculosis Drugs opment are shown in Flow chart 1. Several approaches, such as genome-derived, target-based approaches, phenotypic­ screens at Fluoroquinolones a whole bacterial cell level, multi-target “pathway” screens and Fluoroquinolones are deoxyribonucleic acid (DNA) gyrase redesign/engineering existing scaffolds have been utilized for newer inhibitors. As these drugs are also active against non-replicating, anti-TB drug discovery.6,8 Presently, several newer or repurposed persistent mycobacteria, they are considered to be potentially useful drugs are in pipeline in various stages of development as anti-TB and believed to be important for shortening the duration of TB drug Section 11 Chapter 86 Newer Anti-TB Drugs and Drug Delivery Systems

TABLE 2 │ Newer and repurposed antituberculosis drugs in pipelines12 Drugs in preclinical Drugs in clinical development development Phase I Phase II Phase III Nitroimidazole Oxazolidinone Nitroimidazole oxazine Fluoroquinolones TBA-354 AZD5847 PA-824 Gatifloxacin Caprazene nucleoside Oxazolidinone Moxifloxacin CPZEN-45 (PNU-100480) Nitro-dihydro-imidazooxazole Fluoroquinolone Linezolid Delamanid (OPC67683) Quinolone DC-159a Diarylquinoline Dipiperidine Bedaquiline (TMC207) 4-Thioureido-iminomethylpyridinium SQ609 Ethylenediamine Perchlorate Capuramycin SQ109 Perchlozone SQ641 Rifamycin Benzothiazinone Rifapentine BTZ043 Imidazopyridine Q201 Mepenzolate bromide SPR-10199

Flow chart 1: Stages in drug discovery and development Among the newer fluoroquinolones, there have been several phase IIB trials assessing the utility of substituting moxifloxacin (400 mg once-a-day) in place of any of the first-line drugs with varying results. In a study,13 addition of moxifloxacin to isoniazid, rifampicin and pyrazinamide did not affect the 2-month sputum culture conversion. In another study,14 a small but nonsignificant increase in the week 8 culture negativity was documented. In other studies,15,16 a shorter time to culture conversion has been reported. In a randomized, open-label trial conducted in newly diagnosed sputum smear-positive pulmonary TB patients with moxifloxacin, gatifloxacin or high-dose levofloxacin compared with isoniazid for 7 days has shown good early bactericidal activity (EBA) that was almost comparable to that of isoniazid.17 Several studies are also underway to ascertain the utility of substituting gatifloxacin or moxifloxacin for ethambutol or isoniazid in shortening the duration of treatment from the standard 6 months to 4 months. The outcomes of the ongoing controlled clinical trial comparing the potential of two moxifloxacin- containing regimens to shorten treatment in pulmonary TB (REMOX TB) is likely to further clarify the status of moxifloxacin in the treatment of TB. Rifamycins The newer rifamycins—rifalazil, rifabutin and rifapentine have the same mechanism of action and a significantly improved minimum inhibitory concentration (MIC) as rifampicin.8 Rifalazil has been abandoned due to severe toxicity. Rifabutin has been used as a rifampicin substitute when there is a significant risk of drug-drug interactions. Rifapentine appeared promising drug for shortening the duration of treatment for smear-positive, drug-susceptible pulmonary TB. However, published data suggest that rifapentine has not performed better than rifampicin in the 2-month culture conversion rate raising concerns.5-9 In a phase III treatment-shortening trial in progress twice-weekly rifapentine with moxifloxacin during the continuation phase is being evaluated. Replacement of rifampicin with high-dose rifapentine in the standard first-line regimen is also being evaluated in phase IIb studies.4 The currently used rifampicin daily dose of 600 mg is considered therapy.5-9 These drugs also have the advantage of having minimal not to be on the optimal part of the dose-response curve and some or no interaction with the cytochrome P450 enzyme system. Their workers have suggested that higher doses may be needed to achieve long-term safety and tolerability is also good. However, resistance treatment-shortening goals in patients with drug-sensitive TB.18 to these drugs develops quickly and cross-resistance among them is Several studies are assessing the efficacy of high-dose rifampicin. frequently evident. These include the Rifaquin study (http://rifaquin.wordpress.

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com/); the HIGHRIF project which is a series of 4 trials of high-dose PA-824 rifampicin (http://www.edctp.org); and National Institutes of Health The nitroimidazole-oxazine PA-824 is a derivative of metronidazole. (NIH) supported study in Brazil and Peru.19 Adjuvant therapy with It is hypothesized that PA-824 acts by inhibiting the synthesis of high-dose isoniazid has also been tried for MDR-TB. ketomycolates that are essential components of the mycobacterial Clofazimine cell wall; and by donating nitric oxide during enzymatic nitro reduction within Mycobacterium tuberculosis, thereby poisoning Clofazimine a fat-soluble riminophenazine dye, although developed the respiratory apparatus. A randomized EBA study25 in patients in the 1950s as an anti-TB drug, became established as a key drug for with drug sensitive, smear-positive pulmonary TB patients (n = 69) the treatment of leprosy. Clofazimine is presently being considered evaluating oral PA-824 at 200, 600, 1000 or 1200 mg doses per day for 5-9 for the treatment of X/MDR-TB. It has been used with success in 14 days revealed that all doses were well tolerated, and had exhibited a short, 9-month combined drug regimen for the treatment of MDR- equivalent activity. A subsequent dose-ranging randomized study26 20 TB. in drug-sensitive, sputum smear-positive adult pulmonary TB Other Drugs patients (n = 15) to find the lowest dose giving optimal EBA, oral PA- 824 was administered in doses of 50 mg, 100 mg, 150 mg or 200 mg Among this category, the phenothiazine neuroleptic thioridazine per kg body weight per day for 14 days. PA-824 at a dosage of 100–200 has been used along with other drugs recently with some success in mg daily appeared to be safe and efficacious. the treatment of XDR-TB. Thioridazine is thought to act by enhancing In a recent prospective, randomized EBA study27 from South Africa, the killing of intracellular Mycobacterium tuberculosis by non-killing treatment-naive, drug-susceptible patients with uncomplicated macrophages, inhibiting the genetic expression of efflux pumps of the pulmonary TB were randomized to receive bedaquiline; bedaquiline TB bacillus that extrude prior to reaching their intended and pyrazinamide; PA-824 and pyrazinamide; bedaquiline and targets, and by inhibiting the activity of existing efflux pumps that PA-824; PA-824 along with moxifloxacin and pyrazinamide; or contribute to the multidrug-resistant phenotype of Mycobacterium unmasked standard anti-TB treatment (as positive control). The 21,22 tuberculosis. Several other drugs, such as amoxycillin-clavulanic mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide was found acid, clarithromycin and imipenem have also been used to treat TB to be significantly higher than that of bedaquiline, bedaquiline- 5-9,19 with varying results. pyrazinamide, bedaquiline-PA-824, but not PA-824-pyrazinamide, and comparable with that of standard treatment suggesting that PA- Emerging Newer Antituberculosis Drugs 824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and MDR-TB. Delamanid (OPC-67683) Delamanid (OPC67683) is a nitro-dihydro-imidazooxazole derivative Oxazolidinones that inhibits mycolic acid synthesis with potent in vitro and in vivo The oxazolidinones act via competitive inhibition of the enzyme that activity against drug-resistant strains of Mycobacterium tuberculosis.5-9,19 binds the incoming transfer ribonucleic acid (RNA) with the comple- In a recently published randomized, placebo-controlled, multinational mentary codon on the messenger RNA and inhibiting translation.5-9,19 clinical trial,23 patients with MDR-TB (n = 481) were treated with Cycloserine (4-amino-1,2-oxazolidin-3-one) was the first oxazolidinone delamanid at a dose of 100 mg twice daily (n = 161) or 200 mg twice daily that was used as an anti-TB drug. Another oxazolidinedione, linezolid, (n = 160) or placebo (n = 160) for 2 months in combination with a has been used off-label in the treatment of MDR-TB. In human stud- background drug regimen developed according to WHO guidelines. ies, PNU-100480 (sutezolid) was well tolerated in doses up to 1,200 mg/ Among patients who received 100 mg twice daily delamanid, 45.4% had day. EBA study testing daily 600 mg and 1,200 mg for 14 days has been sputum-culture conversion in liquid broth at 2 months as compared planned. AZD-5847 (posizolid) is scheduled to be evaluated in phase II with 29.6% of patients who received a background drug regimen plus studies in dosages of 500 mg once and twice daily, 800 mg twice daily placebo (p = 0.008). Similarly, patients receiving 200 mg of delamanid and 1,200 mg once daily.5-9,19 twice daily also had a higher proportion of sputum-culture conversion compared with placebo (41.9% vs 29.6%; p = 0.04). These observations Substituted Ethylenediamines suggest that delamanid could enhance treatment options for patients SQ109 is a 1,2-ethylenediamine ethamubutol analog. It acts by with MDR-TB. targeting the cell wall formation but by inhibition of trehalose monophosphate transferase.5-9,19 It exhibits no cross-resistance with Bedaquiline (TMC207) ethambutol. Currently, SQ109 is undergoing safety and efficacy stud- Bedaquiline (TMC207) is a diarylquinoline that targets the proton ies in humans. pump of adenosine triphosphate (ATP) synthase, leading to inadequate synthesis of ATP. In a randomized placebo-controlled Benzothiazinones and Dinitrobenzamides study24 of patients with MDR-TB (n = 47) treated with either Benzothiazinones and dinitrobenzamides act by targeting the bedaquiline or placebo added to the first 8 weeks of a background enzymes responsible for the formation of arabinans that are essential regimen, bedaquiline significantly reduced the time to culture parts of the cell wall. In view of their novel mechanism of action, conversion over 24 weeks (hazard ratio, 2.253; 95% confidence these drugs appear promising as anti-TB drugs. interval, 1.08–4.71; p = 0.031). While only one patient receiving bedaquiline acquired resistance to companion drugs, five patients NEWER ANTITUBERCULOSIS DRUG DELIVERY receiving placebo acquired resistance to companion drugs (4.8% SYSTEMS versus 21.7%; p = 0.18). Resistance to ofloxacin was acquired in four During the last decade, newer drug delivery systems, such as patients receiving placebo and in none receiving bedaquiline (22% liposomes, polymeric micro/nanoparticles and solid lipid nano­ versus 0%; p = 0.066). These observations suggest that bedaquiline particles have been developed.28-30 These newer drug delivery may have the potential to be effective in preventing the emergence systems can be administered through oral, subcutaneous, intra­ of acquired resistance to companion drugs.24 Presently, bedaquiline venous or inhaled route. The newer drug delivery systems have the appears to be a promising new anti-TB drug especially for the potential advantages of improving patient adherence, reduce pill treatment of MDR-TB.5-9,19 burden and shorten the treatment duration. 390 Section 11 Chapter 86 Newer Anti-TB Drugs and Drug Delivery Systems

The term “nanoparticle” refers to a colloidal particle with a size anti-TB drugs as well as inhalable drugs. The therapeutic efficacy of less than 1 micron. Nanoparticles can be made from a wide array of O-stearyl amylopectin (O-SAP)-coated liposomal anti-TB drugs of biocompatible materials, like natural substances (e.g. alginate and given by intravenous route appears promising.28-30 albumin) or synthetic substances (e.g. polylactides, solid lipids).28-30 Inhaled nanoparticle-based administration of anti-TB drugs has the advantages of direct delivery of the drugs to the site of infection, Application of Nanotechnologies for Treatment and bypassing the first-pass metabolism.32 Nanoparticle delivery of Tuberculosis of anti-TB drugs also provides sustained release in both blood plasma as well as organ tissues. Furthermore, as nanoparticles are Translational research has paved the way for the development of preferentially engulfed by the alveolar macrophage, releasing the innovative nanotechnology-based drug delivery systems. Applica­ anti-TB drugs directly into the macrophage and this targeted drug tions of nanotechnologies for the treatment of TB have been listed in delivery holds significant potential in combating the TB bacillus. Table 3 and outlined below. Human clinical trials are awaited in near future to evaluate these Nanodispersions innovative novel modalities of drug delivery and their impact on TB control. Nanosuspensions are submicron colloidal dispersions of pure drugs stabilized with surfactants. Nanonization (reduction of the average FUTURE PROSPECTS size of solid drug particles to the nanoscale by top milling or grind- ing) facilitates improved solubility of drugs that are both with poor With X/MDR-TB emerging as a global threat to TB control, eradication water and lipid solubility. Nanoemulsions are thermodynamically of TB requires not only new drugs and treatment regimens, but newer stable oil-in-water dispersions. Their drop size is between 10 mm drug delivery systems. The repurposed and emerging newer anti-TB and 100 nm and has the advantages of being generated spontane- drugs must be carefully evaluated in well designed controlled clinical ously and ease of production in a large scale and being sterilized by trials so as to generate quality evidence regarding their efficacy. The filtration. Niosomes are thermodynamically stable liposome-like quest for newer and more efficient anti-TB drugs must be pursued vesicles produced with the hydration of cholesterol, charge-inducing relentlessly. components like charged phospholipids and non-ionic surfactants. They can host hydrophilic drugs within the core and lipophilic ones SUMMARY by entrapment in hydrophobic domains. Tuberculosis (TB) has been a leading cause of death since time immemorial and it continues to cause immense human misery Polymeric and Nonpolymeric Nanoparticles even today. The emergence of multidrug-resistant TB (MDR-TB) Polymeric and nonpolymeric nanoparticles have been explored as and extensively drug-resistant TB (XDR-TB) has been threatening to means for drug solubilization, stabilization and targeting, and facilitate destabilize TB control globally. TB has remained a neglected disease two kinds of systems, namely nanocapsules and nanospheres. and since the introduction of rifampicin, anti-TB drug discovery has been sluggish. Since then, no new drug has become available that Polymeric Micelles can be compared to rifampicin in terms of utility and safety. There Polymeric micelles are nanocarriers generated by the self-assembly is an urgent need for new anti-TB drugs that are more effective and of amphiphilic polymers in water above the critical micellar concen- have less toxicity. There is also a need for newer and innovative tration. Dendrimers are macromolecules displaying well defined, anti-TB drug delivery systems. Newer fluoroquinolones, especially regularly hyperbranched and three-dimensional architecture that moxifloxacin has been shown to improve the activity of standard facilitate drug encapsulation. Liposomes are nano- to microsized anti-TB treatment regimen when substituted for ethambutol and is vesicles comprising a phospholipid bilayer that surrounds an aque- studied to shorten the treatment duration in drug-susceptible TB. ous core.31 The hydrophobic domain can be utilized to entrap insolu- Rifapentine is a rifamycin that is being extensively re-evaluated. ble agents and the core enables the encapsulation of water soluble While its potential sterilizing activity has been documented in drugs.31 mice, the same was not evident in a recent short-term clinical trial. Nanoparticles can be formulated as monolithic nanoparticles Clofazimine, a fat-soluble dye with experimental activity against TB, (nanospheres) that embed the drug in the polymeric matrix or is being evaluated for the treatment of MDR-TB. The phenothiazine nanocapsules where the drug is confined within a hydrophobic or neuroleptic thioridazine has been found to be useful for XDR-TB. hydrophilic core surrounded by a definitive “capsule”. Entrapment of Among newer drugs, the nitro-dihydro-imidazooxazole derivative anti-TB drugs in the poly DL-lactide-coglycolide (PLG) microspheres delamanid (OPC67683), the diarylquinoline bedaquiline (TMC207), has been extensively studied. Oral delivery of nanoparticle- the nitroimidazole-oxazine (PA-824) appear most promising. The encapsulated anti-TB drugs has been shown to have several newer oxazolidinones PNU-100480 and AZD-5847 have been shown advantages over the currently used oral drugs in terms of increasing to be as active as linezolid and are less toxic. The ethambutol analogue the efficacy of the administered drugs, reducing degradation in the SQ109 does not have cross-resistance with ethambutol and appears bowels, and increasing uptake and bioavailability. Nanoparticle to have the potential for a synergistic activity in combined regimens. technology also allows intravenous administration of first line Eradication of TB requires not only new drugs and treatment regimens, but newer drug delivery systems, especially those based TABLE 3 │Nanotechnologies applied to the treatment of on nanotechnologies. These newer drug-delivery systems can be tuberculosis administered through oral, subcutaneous, intravenous or inhaled Nanodispersions route. The newer drug delivery systems, especially nanotechnology- • Nanosuspensions based drug delivery systems have the potential advantages of • Nanoemulsions improving patient adherence, reduce pill burden and shorten the • Niosomes treatment duration. Human clinical trials are awaited in near future Polymeric and nonpolymeric nanoparticles to evaluate these innovative novel modalities of drug delivery and Polymeric micelles and other self-assembled structures their impact on TB control.

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