An update on the use of rifapentine for tuberculosis therapy.

Review

An update on the use of rifapentine for tuberculosis therapy 1.

Introduction

2.

Increased dosing frequency of rifapentine: murine, guinea pig and human models

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of British Columbia on 10/11/14 For personal use only.

3.

Shortening TB treatment time with rifapentine: reasons for failure

4.

Novel route of delivery: inhaled anti-tubercular therapy

5.

Conclusions

6.

Expert opinion

John Gar Yan Chan, Xiaoxue Bai & Daniela Traini† †

The University of Sydney, Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, Sydney, Australia

Introduction: Tuberculosis (TB) remains rampant throughout the world, in large part due to the lengthy treatment times of current therapeutic options. Rifapentine, a rifamycin antibiotic, is currently approved for intermittent dosing in the treatment of TB. Recent animal studies have shown that more frequent administration of rifapentine could shorten treatment times, for both latent and active TB infection. However, these results were not replicated in a subsequent human clinical trial. Areas covered: This review analyses the evidence for more frequent administration of rifapentine and the reasons for the apparent lack of efficacy in shortening treatment times in human patients. Inhaled delivery is discussed as a potential option to achieve the therapeutic effect of rifapentine by overcoming the barriers associated with oral administration of this drug. Avenues for developing an inhalable form of rifapentine are also presented. Expert opinion: Rifapentine is a promising active pharmaceutical ingredient with potential to accelerate treatment of TB if delivered by inhaled administration. Progression of current fundamental work on inhaled anti-tubercular therapies to human clinical trials is essential for determining their role in future treatment regimens. While the ultimate goal for global TB control is a vaccine, a short and effective treatment option is equally crucial. Keywords: aerosol, inhalation, rifamycin, rifapentine, tuberculosis Expert Opin. Drug Deliv. (2014) 11(3):421-431

1.

Introduction

Rifapentine properties as an anti-tubercular drug Rifapentine is a semisynthetic cyclopentyl rifamycin antibiotic, generally prescribed for the treatment of tuberculosis (TB), with a serum half-life several times higher than rifampicin, which can provide less frequent dosing in comparison with standard regimens [1]. Similar to other rifamycins, the lipophilic nature of rifapentine allows it to readily diffuse across the bacterial cell membrane where it binds the b-subunit of RNA polymerase, thereby inhibiting the elongation of messenger RNA [2,3]. Importantly, this mechanism also operates against the metabolically dormant bacilli associated with latent TB infection (LTBI) [4,5]. The bactericidal activity of rifapentine is exposure-dependent and related to the area under the concentration-time curve [6], although there is recent suggestion that peak concentrations may be more relevant [7]. Compared with the more commonly used rifampicin, rifapentine is several times more active against Mycobacterium tuberculosis, both in vitro and in vivo [1,8-14]. Its minimum inhibitory concentration ranges from 0.02 to 0.06 µg/ml, depending on the choice of medium and assay [6,9,13,15]. Unfortunately, the shared mechanism of action between rifamycins also leads to extensive cross-resistance, that is, a rifampicin-resistant TB strain would similarly be 1.1

10.1517/17425247.2014.877886 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted

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J. G. Y. Chan et al.

Article highlights. .

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Rifapentine is a cyclopentyl rifamycin derivative with a half-life and anti-tubercular activity several times greater than that of rifampicin. Rifapentine is currently approved by the US FDA for oral administration once or twice weekly for treatment of both active and latent tuberculosis (TB). Recent mouse efficacy studies have demonstrated considerable shortening of treatment time when rifapentine was dosed daily rather than intermittently. Daily dosing of rifapentine failed to accelerate treatment in a guinea pig model of TB infection and human patients, supposedly due to differences in disease pathology between models. Results from further studies are awaited to clarify reasons for treatment failure. A growing collection of research work suggests targeted delivery of rifapentine as an inhaled aerosol to the primary site of TB infection in the lungs may be a viable alternative to realise shortened treatment times for human patients.

This box summarizes key contained in the article.

resistant to rifapentine [9]. Rifamycin resistance is primarily associated with genetic alterations, usually a single base-pair mutation in the 81-bp regions of the RNA polymerase gene [16]. The level of resistance is related to the amino acid position and type of substitution of the b-subunit gene mutation. For example, at amino acid position 516, substitution of aspartate with tyrosine resulted in some resistance to M. tuberculosis, while substitution with valine at the same position led to high-level resistance [17]. Exposure to a single drug results in rapid development of resistance when treating active TB infection (ATBI) and thus rifamycins are always used in combination with other antibiotics [2]. However, in treatment of LTBI where monotherapy is indicated, rifapentine is favoured compared with isoniazid, due to the lower prevalence of rifamycin-resistant bacilli [18]. Combination regimen of rifapentine in TB therapy

1.2

In 1998, the US FDA approved rifapentine (10 mg/kg) as an intermittently orally administered treatment for pulmonary TB [19]. The shorter duration and better adherence to rifapentine-containing regimens is more economically favourable in the long term compared with existing regimens [19,20]. For treatment of LTBI, the use of rifapentine plus isoniazid in a 3-month, once-weekly regimen is supported by clinical evidence [21-23]. A recent Cochrane review found this regimen to be as effective for treating LTBI as the gold standard of 9 months of daily isoniazid, while having less hepatotoxicity and superior adherence rates [24]. Increased implementation of this rifapentine-containing regimen is suggested for treatment of LTBI, although pricing remains a barrier [20]. Interestingly, these results have not readily translated to treatment of active TB. For treatment of ATBI, rifapentine 422

is approved by the FDA at 600 mg dosed orally, twice weekly during the intensive phase of TB treatment (2 months), then once weekly during the continuation phase (4 months) [25]. However, the unacceptably high relapse rates associated with this regimen have limited its use to patients with non-cavity pulmonary infection, and prompted suggestions to use higher doses and more frequent administration [25-27]. There is evidence that increased dosing frequency of rifapentine (Table 1) has the potential to substantially accelerate treatment of ATBI to just 3 months or less [10,28].

Increased dosing frequency of rifapentine: murine, guinea pig and human models

2.

Mice Rosenthal et al. first reported the treatment-shortening potential of daily rifapentine in mice. Mice have been the stalwart in vivo infection model for testing anti-tubercular regimens. Current treatment times with anti-tubercular therapy for humans have a strong correlation with results found in murine models of TB [10,29]. Additionally, serum pharmacokinetics of rifamycins are generally similar to those in humans [28]. Thus, recent results for more frequently administration of rifapentine from these models, of both active and LTBI, are promising. Assuming that the bactericidal activity of rifamycins is related to total drug exposure, an increased rifamycin dose might reduce treatment times. Using a mouse model of ATBI, Rosenthal et al. administered rifapentine (7.5 or 15 mg/kg) in combination with moxifloxacin and pyrazinamide, three or five times a week. These regimens achieved a cure in mice in just 3 months, compared with 6 months necessary to prevent relapse in mice on the standard rifampicincontaining regimen (rifampicin at 10 mg/kg administered five times a week, with isoniazid and pyrazinamide). A follow-up study also for ATBI found that while moxifloxacin achieved greater bactericidal activity than isoniazid after 2 months of treatment, a stable cure was achieved only at 3 months regardless of whether moxifloxacin or isoniazid was used [30]. Thus, treatment-shortening activity for ATBI is primarily associated with the substitution of rifampicin with rifapentine. Concurrent pharmacokinetic studies found that the reduced treatment time was associated with the greater antibiotic exposure due to the long serum half-life of rifapentine [10]. Similar to the findings for ATBI, treatment duration for LTBI might also be reduced. In a murine model of LTBI, 1 month of daily rifapentine, with or without isoniazid, produced similar relapse rates to longer regimens, including 4 months of daily rifampicin and 3 months of once-weekly rifapentine plus isoniazid [31]. These latter two regimens are clinically established alternatives to the gold standard 9-month isoniazid treatment for LTBI [19]. Additionally, if the daily rifapentine regimen was extended to 2 months, a stable cure without any relapse was achieved [31]. 2.1

Expert Opin. Drug Deliv. (2014) 11(3)

An update on the use of rifapentine for TB therapy

Table 1. Recent in vivo efficacy studies of daily-administered rifapentine against TB. Animal model Active TB infection Mouse

Mouse


Mouse

Guinea pig

Human

Latent TB infection Mouse

Mouse

Drugs

Treatment time

Rifapentine (7.5 -- 10 mg/kg) Moxifloxacin Pyrazinamide Rifapentine (10 mg/kg) Moxifloxacin or isoniazid Pyrazinamide Rifapentine (10 mg/kg) Isoniazid Pyrazinamide Rifapentine (100 mg/kg) (equivalent to 10 mg/kg in mice and humans) Isoniazid Pyrazinamide Rifapentine (10 mg/kg) Isoniazid Pyrazinamide Ethambutol Rifapentine (10 mg/kg) Various combinations with: Isoniazid Pyrazinamide Rifapentine (10 mg/kg) Bedaquiline (formerly TMC207)

Year

Ref.

3 months

2007

[10]

3 months

2008

[30]

3 months

2012

[28]

2 months (comparable result with an equivalent dose of rifampicin)

2012

[34]

6 months

2012

[44]

1 -- 2 months

2009

[31]

3 -- 4 months (drug-resistant latent TB infection)

2011

[32]

TB: Tuberculosis.

Finally, when additional antibiotics (pyrazinamide and bedaquiline, respectively) were used with rifapentine, virtually all mice were cured within 1 month. This regimen was also efficacious against drug-resistant TB in 3 -- 4 months [32]. Thus, an ultra-short 1-month LTBI treatment might be possible for drug-susceptible LTBI. A clinical trial (US Clinical Trial Identifier number NCT01404312) is currently underway to compare the efficacy of an ultra-short 4-week daily rifapentine plus isoniazid regimen compared with the standard 9-month isoniazid regimen in HIV-infected patients with LTBI. Although rifamycin pharmacokinetics between mice and humans are similar, the tubercular disease pathology differs notably. The aforementioned studies [10,30-32] utilised BALB/c mice, which, when exposed to M. tuberculosis, do not develop pulmonary granulomas, a key pathological feature of human TB [28]. This crucial difference might impair translation of the treatment-shortening potential of rifapentine to human patients. Thus, Rosenthal et al. performed a dose-ranging study comparing rifapentine and rifampicin between BALB/c and C3HeB/FeJ mice, the latter recently identified to develop human-like hypoxic necrotic granulomas [33]. Interestingly, it was found the bactericidal and sterilising activity of rifapentine against M. tuberculosis was similar in both murine species. Additionally, rifapentine was found to be four times more potent than rifampicin, with its sterilising activity increasing

with dose. Thus, this strengthened the evidence for rifapentine efficacy in human TB. Guinea pigs and humans The promising results from murine studies prompted similar rifapentine-based investigations in TB-infected guinea pigs, which also develop human-like granulomas [34]. Equivalent daily doses of rifapentine or rifampicin were orally administered in combination with isoniazid and pyrazinamide. To account for interspecies pharmacokinetic differences, drug doses for guinea pigs were adjusted to match the exposures achieved in mice and humans [34-36]. In both rifamycin groups, culture-positive relapse was identified at similar rates after 1 month of treatment, while no relapse was detected in guinea pigs treated for 2 months. Thus compared with rifampicin, rifapentine in a daily regimen with companion antibiotics did not enhance bactericidal or sterilising activity in chronically infected guinea pigs. The lack of treatment shortening in guinea pigs foreshadowed similar failure in a related multi-centre human clinical trial (Tuberculosis Trial Consortium Study 29) [28]. This study compared efficacy and safety of rifapentine compared with rifampicin for treatment of ATBI. Rifampicin or rifapentine were administered orally in combination with isoniazid, pyrazinamide and ethambutol. Rifapentine was found to be well tolerated at the administered dose (10 mg/kg). 2.2


423


Oral bioavailability Taken without food, oral bioavailability of rifapentine decreases by 33 – 86%

Systemic dosing High plasma protein binding of rifapentine (98%) limits drug access to sites of infection


Lungs Tuberculosis infection in the lung is primarily extracellular and difficult to treat with systemic antibiotics Liver First pass metabolism. Rifapentine induces its own metabolism Gut Repeated oral rifapentine doses upregulate intestinal P-gp expression, limiting rifapentine absorption

Figure 1. Physiological barriers to efficacy of orally administered rifapentine.

However, at the surrogate end point assessing sputum culture conversion at 2 months, the rifapentine regimen was not more efficacious than the standard treatment regimen with rifampicin. While the use of sputum culture status is indicative of bactericidal efficacy, it may not be a precise indicator of sterilising activity required to prevent relapse [28]. In a murine study, treatment with rifapentine resulted in sterilisation, while rifampicin-containing regimens resulted in relapse [28]. A later or continuous end point will need to be used in future studies.

Shortening TB treatment time with rifapentine: reasons for failure 3.

Potential factors limiting efficacy of rifapentine in humans are outlined in Figure 1. The disparate results obtained between mouse, guinea pig and human studies for rifapentine-based regimens suggest that serum concentrations may be an imperfect surrogate marker for rifapentine efficacy. For example, although the half-life of rifapentine (12 -- 15 h) is significantly higher than rifampicin (2 -- 5 h), it is confounded by high protein binding [34]. As only free drug can diffuse into granulomas, the high protein binding of rifapentine (98%) compared with rifampicin (80%) may negate any advantage when targeting extracellular bacilli in these granulomas [37]. Additionally, rifapentine is known to accumulate intracellularly, being previously found in human monocyte-derived macrophages at concentrations four to five times higher than rifampicin [8]. These factors would have favoured rifapentine exposure and activity against the primarily intracellular infection found in mice, resulting in faster disease resolution than 424

found in guinea pigs and humans. The relatively small size of granulomas present in C3HeB/FeJ mice may explain efficacy comparable with their non-granulomatous BALB/c counterparts [28]. By contrast, high rifapentine protein binding and intracellular accumulation would have a more acute effect in restricting drug access into the larger lesions of guinea pigs and human patients. Thus in these latter studies, serum concentrations may be less representative of actual exposure of M. tuberculosis to rifapentine at some pulmonary sites of infection [34]. The failure of rifapentine to accelerate sputum conversion in Study 29 may also be due to a potentially incorrect association of efficacy with the area under the dose--response curve (AUC). Mitchison and collaborators suggest that antitubercular efficacy of rifapentine is best correlated with peak drug concentrations (Cmax) instead of the AUC. Specifically, rifamycin-tolerant bacilli are commonly found in the sputum of human patients [38]. These persister bacilli with some tolerance to rifapentine would be successively killed off by repeated high peak concentrations, rather than the increased AUC generated by daily dosing of rifapentine. If these mice did not harbour rifamycin-tolerant bacilli, this would explain the discrepancies in results. However, Nuermberger et al. assert otherwise, citing previous studies showing rifamycintolerant bacilli were indeed present in mice infected in these murine studies. Indeed, in the absence of tolerant bacilli much shorter treatment times should otherwise have been achieved, for both rifampicin- and rifapentine-treated mice. Nonetheless, there is a consensus that higher doses of both rifampicin and rifapentine should be investigated [7,39]. Increasing daily doses beyond the administered dose of 10 mg/kg might improve drug access into necrotic granulomas. In mice, steady state serum pharmacokinetics of daily rifapentine was found to be dose-proportional from 20 to 320 mg/kg [28,30,39]. Dooley et al. conducted a human doseranging study to determine the maximum tolerated daily dose of rifapentine. Steady state serum concentrations of rifapentine increased with dose from 5 to 15 mg/kg. However, the pharmacokinetic parameters, including AUC and peak concentration, were not significantly different between 15 and 20 mg/kg. This unexpected finding is particularly concerning, as it suggests that any treatment-shortening potential of rifapentine may not be achievable by oral dosing. This lack of dose-proportional pharmacokinetics in humans might be explained by the diverse disposition of rifapentine between species [40]. First, rifamycins are known to induce their own metabolism in humans. Auto-induction of rifapentine metabolism was previously observed in a human pharmacokinetic study [41]. By contrast, no auto-induction was identified for either rifampicin or rifapentine in guinea pigs [42]. Second, rifapentine is metabolised primarily to 25-desacetyl rifapentine, which has lower activity (10 -- 50% of the parent drug). Comparison of steady state pharmacokinetics showed that while the 25-desacetyl metabolite of rifapentine was identified in guinea pigs and humans, it was




not detected in mice serum [9,42]. Even then, the metabolite was detected at 10 times lower concentrations in guinea pigs than humans. If the rifapentine metabolite competes for binding sites, it may antagonise the activity of rifapentine thus reducing its efficacy. Thus for humans, the combination of metabolic auto-induction and 25-desacetyl metabolite may limit the maximum achievable rifapentine exposure. Rifapentine levels in humans might also be lowered by other factors affecting its bioavailability. In a mouse model, multiple doses of rifampicin were shown to upregulate intestinal P-glycoprotein efflux transporters, leading to reduced oral bioavailability [43]. A similar loss of oral exposure might be expected with rifapentine. Further, dosing of rifapentine without food, as was done in Study 29, reduces oral bioavailability of rifapentine by up to 54% [44-46]. In surprising contrast, rifampicin exposure increases when dosed in a fasting state [44,47]. Thus, in Study 29, this would have disadvantaged rifapentine and contributed to the lack of superior efficacy when compared with an equivalent rifampicin dose. TBTC Study 29PK, an ongoing clinical trial investigating the correlation between free (non-protein bound) rifamycin exposures with anti-mycobacterial activity will give a clearer understanding of the effects of these aforementioned factors on rifapentine pharmacokinetics [42].

Novel route of delivery: inhaled anti-tubercular therapy

4.

Overview Given the current uncertainty over therapeutic efficacy with orally dosed rifapentine, an alternative approach, such as targeted inhaled administration of rifapentine, might achieve improved anti-tubercular efficacy. An inhaled formulation could be advantageous for the treatment of TB by improving local and systemic dosing compared with the oral route. It would maximise drug delivery to pulmonary granulomas and infected alveolar macrophages, which would otherwise be limited by plasma protein binding when dosed orally [48]. Additionally, more efficient systemic dosing would be expected as rifapentine would absorb directly into the bloodstream, bypassing intestinal efflux pumps, variability with food intake and hepatic first-pass metabolism, perhaps even giving dose-proportional serum pharmacokinetics [49,50]. Serum rifapentine bioavailability is important for treating any disseminated infection [51]. Finally, apart from clear potential treatment advantages, it is a non-invasive route of administration, which is important for increasing patient acceptance and compliance. There is a growing research inventory on the formulation and delivery of anti-tubercular drugs to the pulmonary site of primary infection [29,42,50-65]. In a mouse model of TB, antibiotics for TB (isoniazid, capreomycin and amikacin) delivered into the lungs as an aerosol, have shown comparable pulmonary bacterial load reduction with oral or intravenous delivery, even when administered at a lower dose and reduced 4.1

frequency [42]. Inhaled clofazimine and rifampicin have also been shown to be effective against TB in mice [65,66]. In TBinfected guinea pigs, a smaller number of pulmonary bacilli and granulomas were found in lungs of TB-infected guinea pigs after insufflation with dry powder capreomycin, compared with higher doses administered intravenously or intramuscularly [51]. Similarly, anti-tubercular efficacy was comparable between insufflated bedaquiline (formerly PA-824) dry powder and a higher oral dose in guinea pigs [67]. These studies demonstrate the potential efficacy of inhaled anti-tubercular therapy. In addition to efficacy, various studies have also shown favourable in vivo pharmacokinetics for inhaled antitubercular drugs, including rifamycins [60-62,68]. This includes a recent Phase I human clinical trial to identify a suitable inhaled dose of capreomycin [53]. In anticipation of inhaled anti-tubercular therapy, a recent review outlines methods of translating such basic research into clinical outcomes, and ultimately product development [69]. Thus, an inhalable form of rifapentine might be a promising alternative to current oral administration. Inhaled rifapentine Although inhalable formulations of rifampicin and rifabutin are well-studied [50,52,55-59,62-65,70,71], there are limited data on rifapentine delivered to the lungs. This may be due to the relatively limited use of rifapentine compared with rifampicin and being recently established as intermittent oral therapy. Furthermore, evidence suggesting more frequently administered rifapentine to have better efficacy than rifampicin, is still fairly recent [10,28,30,31,72]. Two studies that focus on pulmonary delivery of controlled-release rifapentine formulations by bronchoscopy were identified [73,74]. Shu et al. optimised rifapentinecontaining liposomes with lauric diethanolamide as a surfactant. Resulting liposomes had sizes between 14 and 50 nm and drug loading up to 58%. Delivered as a suspension by bronchoscopy, the formulation demonstrated improved drug penetration of pig lung tissue and rapidly resolved tubercular infection at targeted granulomatous sites. Another study by Yang utilised electrostatic droplet generation to produce sustained-release sodium alginate particles with rifapentine loading of 22%. Particle sizes were ranged from 90 to 110 µm. Rifapentine sodium alginate particles suspended in saline were administered directly onto infected foci in the lungs of beagle dogs. Sustained drug concentrations were maintained in these dosed areas of lung tissue for up to 7 days, with several times higher concentration than in the plasma. However, the specific targeting associated with bronchoscopy was not intended to kill all pulmonary bacilli and instead would be used as companion treatment to oral therapy. Additionally, it would be highly impractical and difficult to administer rifapentine by bronchoscopy, even to hospitalised patients. Instead, a more logical option would be inhalable rifapentine developed for self-administration, which could readily 4.2


425


Table 2. Recent inhalable rifamycin-containing dry powders for tuberculosis.


Drug(s)

Vehicle/excipients

Method of manufacture

Year

Ref.

Rifampicin Rifampicin Isoniazid Pyrazinamide Rifampicin Rifampicin

None None

Spray drying Spray drying

2011 2013

[70] [91]

Lactose PLGA

2013 2011

[92] [93]

Rifampicin Rifampicin Rifampicin Rifampicin Rifampicin Rifampicin Isoniazid Rifabutin Rifabutin Isoniazid

PLGA PLGA, sodium alginate PLGA, sucrose palmitate PLGA, PLA Eudragit Acryloyl chloride

Supercritical antisolvent-drug excipient mixing Solvent evaporation with premix membrane homogenisation Solvent evaporation Solvent evaporation Emulsion-solvent evaporation Spray drying Emulsion solvent diffusion Suspension radical polymerisation

2009 2012 2012 2012 2010 2011

[94] [95] [96] [71] [97] [98]

Tristearin, soya-lecithin, mannose PLA

Solvent injection Spray drying

2009 2012

[99] [68]

PLA: Poly(lactic acid); PLGA: Poly(lactic-co-glycolic) acid.

Figure 2. Scanning electron microscopy image of inhalable rifapentine crystals.

be adapted from existing inhalable rifamycin-containing formulations (Table 2). Inhalable controlled-release formulations of rifamycins have previously included alginate and liposomal encapsulation for nebulisation [75-78]. However, a more practical and popular approach is polymeric rifamycin-containing dry powders, which have been described extensively in literature [52,56-58,62,64,65,68,71]. The use of dry powders allow for greater dose delivery and better stability for rifamycins, which can undergo hydrolysis [79]. Additionally, polymeric microparticles, which are expected to target phagocytosed bacilli, were found non-toxic to macrophage cells in vitro [52,80]. Pharmacokinetic studies delivering poly(lactic acid) (PLA) microparticles, containing both rifampicin and isoniazid, have demonstrated enhanced drug targeting to the lungs and alveolar macrophages of mice and macaques [62,68]. 426

Rifampicin-containing poly(lactic-co-glycolic) acid (PLGA) particles administered prior to aerosol infection, reduced the number of tubercular bacteria and lung damage in guinea pigs compared with control animals [65]. Another study evaluated the optimal dosing regimen of these rifampicin-PLGA microparticles administered to TB-infected guinea pigs, finding efficacy of a single dose similar to that of multiple nebulised doses of non-encapsulated rifampicin [81]. Finally, Coowanitwong et al. extensively covers the in vivo effects of modifying various polymers (both PLA and PLGA, respectively) to readily tailor and optimise the release rate for rifamycin-containing microparticles in rats [52]. Thus, a comprehensive database exists for developing rifapentinecontaining polymer microparticles suitable for inhalation. Alternatively, a pure drug formulation may be favoured to maximise rifapentine delivery to the patient. Son and McConville compared an amorphous to crystalline form of rifampicin. Superior chemical stability and aerosol dispersion performance was identified for the crystalline form [70]. In our own investigations, a similar comparison for the two forms of rifapentine, with similar positive findings for the crystalline form (Figure 2) was performed. Additionally, pulmonary delivery of respirable-sized crystalline rifapentine dry powder to mice (20 mg/kg) resulted in considerably enhanced lung retention attributed to the intracellular accumulation of rifapentine. By contrast, Mizoe et al. found that rifampicin microparticles, with or without excipients, delivered to the lungs of rats, were eliminated from the lungs and systemic circulation in < 4 h. This may be due to the low doses used (2.5 mg/kg rifampicin) and the relatively less hydrophobic nature of rifampicin resulting in approximately four times lower intracellular accumulation compared with rifapentine [8,55]. The limited pulmonary residence time of rifampicin suggests it is more suited to a controlled-release



formulation. By contrast, the more favourable pharmacokinetics of rifapentine including its substantially longer serum half-life and higher intracellular accumulation warrants further investigation as either a pure or modified-release aerosol formulation.


5.

Conclusions

Rifapentine dosed more frequently than the standard regiment for the treatment of TB is of interest due to its FDA-approved use as a first-line anti-tubercular drug and established clinical profile. However, recent evidence shows several discrepancies between murine and human models. In addition, the pharmacokinetics of rifapentine in humans is still not well understood and warrants further investigation. An alternate inhaled route of delivery of rifapentine could solve many problems associated with the current oral administration of rifapentine and improve its efficacy resulting in shorter TB treatment times. 6.

Expert opinion

The current approved use of rifapentine as an intermittent therapy in a 6-month regimen represents an important step towards shorter and simpler anti-tubercular treatment options. Recent animal studies suggest switching these intermittent doses into more frequent administration may cure active and LTBI in 3 months or less. However, these results obtained in murine models have not been reproduced in humans, suggesting much still remains to be understood. Of interest is whether rifapentine activity is best correlated with total exposure (AUC) or peak concentrations (Cmax), and understanding the lack of dose-proportional pharmacokinetics in human subjects. In addition, elucidating whether the required pulmonary concentrations of rifapentine for treatment shortening can be achieved by oral administration is still not known. This knowledge would allow for the strategic design of novel rifapentine-containing regimens with enhanced therapeutic efficacy. There is some evidence to suggest that inhaled administration may be a key aspect in optimising anti-tubercular drug activity in the pulmonary site of infection. However, while there are compelling animal data for inhaled anti-tubercular therapy, the human clinical data are virtually non-existent, with only one pharmacokinetic study at the time of writing. Additionally, only a small amount of work has focused on inhaled rifapentine due to the recent nature of evidences suggesting it to be superior to the more commonly used

rifampicin. An analysis of the economic viability and practical aspects of implementing an inhaled therapy for TB would also be helpful. Thus, key goals are to increase investigation of rifapentine as an inhaled therapy and to drive the translation of existing fundamental research on inhaled anti-tubercular drugs from bench and animal study to clinical trials. Such studies would determine whether targeted pulmonary treatment of TB could radically shorten the current 6-month treatment regimen and provide considerably improved global control of the disease. Additionally, it would have implications for determining the optimal route of administration for newly developed anti-tubercular drugs. Definitively, the development of a working vaccine for TB remains the ultimate goal. Interestingly, there is some investigation into whether such a vaccine might be more efficacious via inhaled delivery, as it mimics the primary route of TB transmission. However, even if a vaccine was to be achieved in the near future, the biggest challenge remains to cater to the needs of the one-third of the world that is already infected with TB. To do this effectively, a treatment option that takes weeks, not months, would be essential. Such a short treatment time is expected to comprise novel drugs with significantly improved anti-tubercular activity. A number of new anti-tubercular drugs are in the pipeline [82-89]. Another trend would be the replacement of the two key drugs in the current standard regimen -- isoniazid and rifampicin -- due to the increasing number of drugresistant strains. A regimen consisting of PA-824, bedaquiline and pyrazinamide has recently been tested in a clinical trial and found to be as efficacious as the current standard therapy [90]. Finally, if the inhaled route is found to improve the activity of anti-tubercular drugs, it may be implemented either as an adjunct to oral therapy or even as a primary therapy, provided efficacious blood concentrations can be achieved. As such, we expect to see expanding research into drug only, combination or controlled-release anti-tubercular formulations.

Acknowledgement X Bai and JGY Chan contributed equally to this work.

Declaration of interest JGY Chan is a recipient of Australian Postgraduate Award from the Australian federal Government. D Traini is a recipient of an Australian Research council Future Fellowship project number FT1201010063.


427


Bibliography

tuberculosis complex. J Antimicrob Chemother 2000;46(4):571-6

Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.


2.

Arioli V, Berti M, Carniti G, et al. Antibacterial activity of DL 473, a new semisynthetic rifamycin derivative. J Antibiot (Tokyo) 1981;34(8):1026-32 Munsiff SS, Kambili C, Ahuja SD. Rifapentine for the treatment of pulmonary tuberculosis. Clin infect Dis 2006;43(11):1468-75

3.

Wade MM, Zhang Y. Mechanisms of drug resistance in Mycobacterium tuberculosis. Front Biosci 2004;9:975-94

4.

Mitchison DA. Basic mechanisms of chemotherapy. Chest 1979;76(6 Suppl):771-81

5.

Dickinson JM, Mitchison DA. Experimental models to explain the high sterilizing activity of rifampin in the chemotherapy of tuberculosis. Am Rev Respir Dis 1981;123(4 Pt 1):367-71

6.

7.

8.

9.

10.

11.

428

van Ingen J, Aarnoutse RE, Donald PR, et al. Why do we use 600 mg of rifampicin in tuberculosis treatment? Clin infect Dis 2011;52(9):e194-9

12.

13.

14.

15.

16.

Mitchison DA. Pharmacokinetic/ pharmacodynamic parameters and the choice of high-dosage rifamycins. Int J Tuberc Lung Dis 2012;16(9):1186-9 Mor N, Simon B, Mezo N, et al. Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages. Antimicrob Agents Chemother 1995;39(9):2073-7 Rastogi N, Goh KS, Berchel M, et al. Activity of rifapentine and its metabolite 25-O-desacetylrifapentine compared with rifampicin and rifabutin against Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis and M. bovis BCG. J Antimicrob Chemother 2000;46(4):565-70 Rosenthal IM, Zhang M, Williams KN, et al. Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model. PLoS Med 2007;4(12):e344 Bemer-Melchior P, Bryskier A, Drugeon HB. Comparison of the in vitro activities of rifapentine and rifampicin against Mycobacterium

17.

Ji B, Truffot-Pernot C, Lacroix C, et al. Effectiveness of rifampin, rifabutin, and rifapentine for preventive therapy of tuberculosis in mice. Am Rev Respir Dis 1993;148(6 Pt 1):1541-6 Heifets LB, Lindholm-Levy PJ, Flory MA. Bactericidal activity in vitro of various rifamycins against Mycobacterium avium and Mycobacterium tuberculosis. Am Rev Respir Dis 1990;141(3):626-30 Sirgel FA, Fourie PB, Donald PR, et al. The early bactericidal activities of rifampin and rifapentine in pulmonary tuberculosis. Am J Respir Crit Care Med 2005;172(1):128-35 Dickinson JM, Mitchison DA. In vitro properties of rifapentine (MDL473) relevant to its use in intermittent chemotherapy of tuberculosis. Tubercle 1987;68(2):113-18 Moghazeh SL, Pan X, Arain T, et al. Comparative antimycobacterial activities of rifampin, rifapentine, and KRM-1648 against a collection of rifampin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations. Antimicrob Agents Chemother 1996;40(11):2655-7 Bodmer T, Zurcher G, Imboden P, et al. Mutation position and type of substitution in the beta-subunit of the RNA polymerase influence in-vitro activity of rifamycins in rifampicinresistant Mycobacterium tuberculosis. J Antimicrob Chemother 1995;35(2):345-8

18.

Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 2000;4(9):796-806

19.

Holland DP, Sanders GD, Hamilton CD, et al. Costs and costeffectiveness of four treatment regimens for latent tuberculosis infection. Am J Respir Crit Care Med 2009;179(11):1055-60

20.

Holland DP, Sanders GD, Hamilton CD, et al. Potential economic viability of two proposed rifapentinebased regimens for treatment of latent tuberculosis infection. PLoS One 2011;6(7):e22276


21.

de Castilla DL, Rakita RM, Spitters CE, et al. Short-course isoniazid plus rifapentine directly observed therapy for latent tuberculosis in solid-organ transplant candidates. Transplantation 2013. [Epub ahead of print]

22.

Sterling TR, Villarino ME, Borisov AS, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365(23):2155-66

23.

Bemis K, Lobato M, Sosa L. Use of 12-Dose Isoniazid and Rifapentine for the Treatment of Latent Tuberculosis in Connecticut. 2013 CSTE Annual Conference; California; 2013

24.

Sharma SK, Sharma A, Kadhiravan T, et al. Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIVnegative people at risk of active TB. Cochrane Database Syst Rev 2013;7:CD007545

25.

Dooley KE, Bliven-Sizemore EE, Weiner M, et al. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers. Clin Pharmacol Ther 2012;91(5):881-8

26.

Gao XF, Li J, Yang ZW, et al. Rifapentine vs. rifampicin for the treatment of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis 2009;13(7):810-19

27.

Centers for Disease Control and Prevention (CDC). Treatment of tuberculosis. Atlanta, USA; 2003

28.

Rosenthal IM, Tasneen R, Peloquin CA, et al. Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis. Antimicrob Agents Chemother 2012;56(8):4331-40 Murine efficacy study demonstrating rifapentine shortening treatment time for active tuberculosis infection even in granuloma-forming mice.

.

29.

Dorman SE, Johnson JL, Goldberg S, et al. Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2009;180(3):273-80

30.

Rosenthal IM, Zhang M, Grosset JH, et al. Rifapentine-containing regimens cure murine tuberculosis in weeks rather


.

31.


.

32.

33.

34.

.

35.

36.

than months. Am J Respir Crit Care Med 2008;177:A789 Murine efficacy study demonstrating rifapentine shortening treatment time for active tuberculosis infection.

40.

Zhang T, Zhang M, Rosenthal IM, et al. Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection. Am J Respir Crit Care Med 2009;180(11):1151-7 Murine efficacy study demonstrating rifapentine shortening treatment time for latent tuberculosis infection.

41.

Zhang T, Li SY, Williams KN, et al. Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection. Am J Respir Crit Care Med 2011;184(6):732-7

42.

Harper J, Skerry C, Davis SL, et al. Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions. J Infect Dis 2012;205(4):595-602 Dutta NK, Illei PB, Peloquin CA, et al. Rifapentine is not more active than rifampin against chronic tuberculosis in guinea pigs. Antimicrob Agents Chemother 2012;56(7):3726-31 Guinea pig efficacy study demonstrating rifapentine did not shorten treatment time for active tuberculosis infection compared with rifampicin. Ahmad Z, Klinkenberg LG, Pinn ML, et al. Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig. J Infect Dis 2009;200(7):1136-43 Ahmad Z, Nuermberger EL, Tasneen R, et al. Comparison of the ‘Denver regimen’ against acute tuberculosis in the mouse and guinea pig. J Antimicrob Chemother 2010;65(4):729-34

37.

Aristoff PA, Garcia GA, Kirchhoff PD, et al. Rifamycins--obstacles and opportunities. Tuberculosis 2010;90(2):94-118

38.

Coates AR, Hu Y, Jindani A, et al. Contradictory results with high-dosage rifamycin in mice and humans. Antimicrob Agents Chemother 2013;57(2):1103

39.

rifamycin in mice and humans. Antimicrob Agents Chemother 2013;57(2):1104-5

Nuermberger EL, Rosenthal IM, Tasneen R, et al. Reply to Contradictory results with high-dosage

43.

44.

..

Emary WB, Toren PC, Mathews B, et al. Disposition and metabolism of rifapentine, a rifamycin antibiotic, in mice, rats, and monkeys. Drug Metab Dispos 1998;26(8):725-31 Dooley K, Flexner C, Hackman J, et al. Repeated administration of high-dose intermittent rifapentine reduces rifapentine and moxifloxacin plasma concentrations. Antimicrob Agents Chemother 2008;52(11):4037-42 Dutta NK, Alsultan A, Peloquin CA, et al. Preliminary pharmacokinetic study of repeated doses of rifampin and rifapentine in guinea pigs. Antimicrob Agents Chemother 2013;57(3):1535-7 Hosagrahara V, Reddy J, Ganguly S, et al. Effect of repeated dosing on rifampin exposure in BALB/c mice. Eur J Pharm Sci 2013;49(1):33-8 Dorman SE, Goldberg S, Stout JE, et al. Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium. J Infect Dis 2012;206(7):1030-40 Multi-centre human clinical trial comparing oral rifampicin and rifapentine for treatment of tuberculosis.

45.

Temple ME, Nahata MC. Rifapentine: its role in the treatment of tuberculosis. Ann Pharmacother 1999;33(11):1203-10

46.

Zvada SP, Van Der Walt JS, Smith PJ, et al. Effects of four different meal types on the population pharmacokinetics of single-dose rifapentine in healthy male volunteers. Antimicrob Agents Chemother 2010;54(8):3390-4

47.

Peloquin CA, Namdar R, Singleton MD, et al. Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids. Chest 1999;115(1):12-18

48.

Pandey R, Khuller GK. Antitubercular inhaled therapy: opportunities, progress and challenges. J Antimicrob Chemother 2005;55(4):430-5

49.

Mathias NR, Hussain MA. Non-invasive systemic drug delivery: developability considerations for alternate routes of


administration. J Pharm Sci 2010;99(1):1-20 50.

Misra A, Hickey AJ, Rossi C, et al. Inhaled drug therapy for treatment of tuberculosis. Tuberculosis 2011;91(1):71-81

51.

Garcia-Contreras L, Fiegel J, Telko MJ, et al. Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model. Antimicrob Agents Chemother 2007;51(8):2830-6

52.

Coowanitwong I, Arya V, Kulvanich P, et al. Slow release formulations of inhaled rifampin. AAPS J 2008;10(2):342-8

53.

Dharmadhikari AS, Kabadi M, Gerety B, et al. Phase I, single-dose, dose-escalating study of inhaled dry powder capreomycin: a new approach to therapy of drug-resistant tuberculosis. Antimicrob Agents Chemother 2013;57(6):2613-19

54.

Weiner M, Bock N, Peloquin CA, et al. Pharmacokinetics of rifapentine at 600, 900, and 1,200 mg during once-weekly tuberculosis therapy. Am J Respir Crit Care Med 2004;169(11):1191-7

55.

Mizoe T, Ozeki T, Okada H. Application of a four-fluid nozzle spray drier to prepare inhalable rifampicincontaining mannitol microparticles. AAPS PharmSciTech 2008;9(3):755-61

56.

Muttil P, Kaur J, Kumar K, et al. Inhalable microparticles containing large payload of anti-tuberculosis drugs. Eur J Pharm Sci 2007;32(2):140-50

57.

O’Hara P, Hickey AJ. Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: manufacture and characterization. Pharm Res 2000;17(8):955-61

58.

Sharma R, Saxena D, Dwivedi AK, et al. Inhalable microparticles containing drug combinations to target alveolar macrophages for treatment of pulmonary tuberculosis. Pharm Res 2001;18(10):1405-10

59.

Sharma R, Yadav AB, Muttil P, et al. Inhalable microparticles modify cytokine secretion by lung macrophages of infected mice. Tuberculosis 2011;91(1):107-10

60.

Sung JC, Garcia-Contreras L, Verberkmoes JL, et al. Dry powder nitroimidazopyran antibiotic PA-824

429



aerosol for inhalation. Antimicrob Agents Chemother 2009;53(4):1338-43

70.

Son YJ, McConville JT. A new respirable form of rifampicin. Eur J Pharm Biopharm 2011;78(3):366-76

61.

Tsapis N, Bennett D, O’Driscoll K, et al. Direct lung delivery of paraaminosalicylic acid by aerosol particles. Tuberculosis 2003;83(6):379-85

71.

Son YJ, McConville JT. Preparation of sustained release rifampicin microparticles for inhalation. J Pharm Pharmacol 2012;64(9):1291-302

62.

Verma RK, Kaur J, Kumar K, et al. Intracellular time course, pharmacokinetics, and biodistribution of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to mice. Antimicrob Agents Chemother 2008;52(9):3195-201

72.

Zhang M, Li SY, Rosenthal IM, et al. Treatment of tuberculosis with rifamycin-containing regimens in immune-deficient mice. Am J Respir Crit Care Med 2011;183(9):1254-61

63.

64.

65.

66.

67.

68.

69.

430

Verma RK, Singh AK, Mohan M, et al. Inhaled therapies for tuberculosis and the relevance of activation of lung macrophages by particulate drug-delivery systems. Ther Deliv 2011;2(6):753-68 Yadav AB, Sharma R, Muttil P, et al. Inhalable microparticles containing isoniazid and rifabutin target macrophages and ‘stimulate the phagocyte’ to achieve high efficacy. Indian J Exp Biol 2009;47(6):469-74 Suarez S, O’Hara P, Kazantseva M, et al. Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: screening in an infectious disease model. Pharm Res 2001;18(9):1315-19 Ziakas PD, Mylonakis E. 4 months of rifampin compared with 9 months of isoniazid for the management of latent tuberculosis infection: a meta-analysis and cost-effectiveness study that focuses on compliance and liver toxicity. Clin infect Dis 2009;49(12):1883-9 Garcia-Contreras L, Sung JC, Muttil P, et al. Dry powder PA-824 aerosols for treatment of tuberculosis in guinea pigs. Antimicrob Agents Chemother 2010;54(4):1436-42 Kumar Verma R, Mukker JK, Singh RS, et al. Partial biodistribution and pharmacokinetics of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to rhesus macaques. Mol Pharm 2012;9(4):1011-16 Hickey AJ, Misra A, Fourie PB. Dry powder antibiotic aerosol product development: inhaled therapy for tuberculosis. J Pharm Sci 2013;102(11):3900-7

73.

74.

75.

76.

Shu JY, Quan XY, Shu Y, et al. Preparation, characterization, and pulmonary delivery of rifapentine liposomes modified by lauric diethanolamide. Yao Xue Xue Bao 2006;41(8):761-4 Yang Z. Study on rifapentine-sodium alginate microspheres for lung targeting drug delivery [PhD]. Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China; 2011 Pandey R, Sharma S, Khuller GK. Nebulization of liposome encapsulated antitubercular drugs in guinea pigs. Int J Antimicrob Agents 2004;24(1):93-4 Ahmad Z, Sharma S, Khuller GK. Inhalable alginate nanoparticles as antitubercular drug carriers against experimental tuberculosis. Int J Antimicrob Agents 2005;26(4):298-303

treatment of tuberculosis in the guinea pig. J Antimicrob Chemother 2006;58(5):980-6 82.

Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med 2012;366(23):2151-60

83.

Singh R, Manjunatha U, Boshoff HI, et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 2008;322(5906):1392-5

84.

Nikonenko BV, Protopopova M, Samala R, et al. Drug therapy of experimental tuberculosis (TB): improved outcome by combining SQ109, a new diamine antibiotic, with existing TB drugs. Antimicrob Agents Chemother 2007;51(4):1563-5

85.

Lanoix JP, Nuermberger E. Sutezolid, oxazolidinone antibacterial treatment of tuberculosis. Drug Fut 2013;38(6):387-94

86.

Salomon JJ, Galeron P, Schulte N, et al. Biopharmaceutical in vitro characterization of CPZEN-45, a drug candidate for inhalation therapy of tuberculosis. Ther Deliv 2013;4(8):915-23

87.

Hoshino K, Inoue K, Murakami Y, et al. In vitro and in vivo antibacterial activities of DC-159a, a new fluoroquinolone. Antimicrob Agents Chemother 2008;52(1):65-76

77.

Vyas SP, Kannan ME, Jain S, et al. Design of liposomal aerosols for improved delivery of rifampicin to alveolar macrophages. Int J Pharm 2004;269(1):37-49

88.

78.

Gursoy A, Kut E, Ozkirimli S. Co-encapsulation of isoniazid and rifampicin in liposomes and characterization of liposomes by derivative spectroscopy. Int J Pharm 2004;271(1-2):115-23

Nikonenko BV, Reddy VM, Protopopova M, et al. Activity of SQ641, a capuramycin analog, in a murine model of tuberculosis. Antimicrob Agents Chemother 2009;53(7):3138-9

89.

Balasubramanian V, Solapure S, Iyer H, et al. Bactericidal activity and mechanism of action of AZD5847: a novel oxazolidinone for the treatment of tuberculosis. Antimicrob Agents Chemother 2013. [Epub ahead of print]

90.

Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet 2012;380(9846):986-93

91.

Chan JG, Chan HK, Prestidge CA, et al. A novel dry powder inhalable

79.

Prankerd RJ, Walters JM, Parnes JH. Kinetics for degradation of rifampicin, an azomethine-containing drug which exhibits reversible hydrolysis in acidic solutions. Int J Pharm 1992;78(1):59-67

80.

Hirota K, Hasegawa T, Nakajima T, et al. Delivery of rifampicin-PLGA microspheres into alveolar macrophages is promising for treatment of tuberculosis. J Control Release 2010;142(3):339-46

81.

Garcia-Contreras L, Sethuraman V, Kazantseva M, et al. Evaluation of dosing regimen of respirable rifampicin biodegradable microspheres in the



formulation incorporating three first-line anti-tubercular antibiotics. Eur J Pharm Biopharm 2012. [Epub ahead of print] 92.


93.

94.

Ober CA, Kalombo L, Swai H, et al. Preparation of rifampicin/lactose microparticle composites by a supercritical antisolvent-drug excipient mixing technique for inhalation delivery. Powder Technol 2013;236:132-8 Doan TV, Couet W, Olivier JC. Formulation and in vitro characterization of inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery. Int J Pharm 2011;414(1-2):112-17 Sung JC, Padilla DJ, Garcia-Contreras L, et al. Formulation and pharmacokinetics of self-assembled rifampicin nanoparticle systems for pulmonary delivery. Pharm Res 2009;26(8):1847-55

95.

96.

Hu C, Feng H, Zhu C. Preparation and characterization of rifampicin-PLGA microspheres/sodium alginate in situ gel combination delivery system. Colloids Surf B Biointerfaces 2012;95:162-9 Diab R, Brillault J, Bardy A, et al. Formulation and in vitro characterization of inhalable polyvinyl alcohol-free rifampicin-loaded PLGA microspheres prepared with sucrose palmitate as stabilizer: efficiency for ex vivo alveolar macrophage targeting. Int J Pharm 2012;436(1-2):833-9

97.

Bhise SB, More AB, Malayandi R. Formulation and in vitro evaluation of rifampicin loaded porous microspheres. Sci Pharm 2010;78(2):291-302

98.

Cassano R, Trombino S, Ferrarelli T, et al. Respirable rifampicin-based microspheres containing isoniazid for


tuberculosis treatment. J Biomed Mater Res A 2011. [Epub ahead of print] 99.

Nimje N, Agarwal A, Saraogi GK, et al. Mannosylated nanoparticulate carriers of rifabutin for alveolar targeting. J Drug Target 2009;17(10):777-87

Affiliation John Gar Yan Chan1 BPharm (Hons), Xiaoxue Bai2 MM & Daniela Traini†1 PhD † Author for correspondence 1 The University of Sydney, Respiratory Technology, Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, NSW 2037, Sydney, Australia Tel: +61 2 91140352; E-mail: [email protected] 2 The First Clinical Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, Jilin, 130000, China

431

An Update on Global Tuberculosis (TB).

Short-course isoniazid plus rifapentine directly observed therapy for latent tuberculosis in solid-organ transplant candidates.

Update on cutaneous tuberculosis.

An update on mechanical circulatory support for heart failure therapy.

Update on therapy for narcolepsy.

An update on male hypogonadism therapy.

The effect of cannabis use on memory function: an update.

An update on the benefits and risks of rosuvastatin therapy.

Meaningful use: an update for physiatry practices.

Therapy for cutaneous melanoma: an update.

Rifapentine-linezolid-loaded PLGA microspheres for interventional therapy of cavitary pulmonary tuberculosis: preparation and in vitro characterization.

[Update on the epidemiology, diagnosis and therapy of tuberculosis in HIV-infected patients].

An update on the use of immunoglobulin for the treatment of immunodeficiency disorders.

An update on the use of lenalidomide for the treatment of multiple myeloma.

Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial.

Update on pharmacologic therapy for pulmonary embolism.

Update on medical therapy for male LUTS.

Update on the use of rituximab for intractable rheumatoid arthritis.

Development and in vitro characterization of drug delivery system of rifapentine for osteoarticular tuberculosis.

Update on Oral Appliance Therapy for OSA.

Update on the therapy of Behçet disease.

Update on cost-effectiveness of a 12-dose regimen for latent tuberculous infection at new rifapentine prices.

Hormone therapy in menopause: An update on cardiovascular disease considerations.

Posaconazole: An Update of Its Clinical Use.