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Bedaquiline and delamanid in tuberculosis a

a

b

Susanna Esposito , Sonia Bianchini & Francesco Blasi a 1

Università degli Studi di Milano, Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy +39 02 55 03 24 98; +39 02 50 32 02 06; b 2

Università degli Studi di Milano, Pneumology Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy Published online: 19 Aug 2015.

Click for updates To cite this article: Susanna Esposito, Sonia Bianchini & Francesco Blasi (2015): Bedaquiline and delamanid in tuberculosis, Expert Opinion on Pharmacotherapy To link to this article: http://dx.doi.org/10.1517/14656566.2015.1080240

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Invited Review

Bedaquiline and delamanid in tuberculosis

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Susanna Esposito†, Sonia Bianchini & Francesco Blasi 1.

Introduction

2.

Bedaquiline

3.

Delamanid

4.

Conclusion

5.

Expert opinion

†

Universit
a degli Studi di Milano, Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

Introduction: In recent years, a pressing need to develop new, effective and safe drugs against tuberculosis (TB) has continued. Poor adherence to a long therapeutic regimen against TB, intermittent drug use, errors in medical prescriptions, low quality of old TB drugs and ineffective TB control have led to the emergence of resistant TB. Areas covered: Two new drugs have gained importance and seem promising against resistant TB: bedaquiline and delamanid. This review summarizes the main characteristics of these two drugs and their role in TB management. Expert opinion: Bedaquiline and delamanid appear to be promising new anti-TB drugs. Due to a mechanism of action that is different from that of other available drugs, their efficacy has appeared optimal in cases of adults with resistant pulmonary TB. Although their pharmacokinetic and pharmacodynamic profiles seem optimal, potential cardiologic side effects such as QT-interval prolongation have been associated with their use. However, specific studies performed in the pediatric population are needed to confirm these results. This seems particularly important considering the long duration of TB treatment required for resistant TB as well as the potential interactions with other drugs included in anti-TB regimens or administered for an underlying comorbidity. Keywords: bedaquiline, children, delamanid, extensively drug-resistant tuberculosis, multidrugresistant tuberculosis, pediatric tuberculosis, tuberculosis Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Tuberculosis (TB), HIV infection and malaria are considered the most important epidemiological issues worldwide [1]. Before the 1940s, TB chemotherapy was not available. In 1944, streptomycin was isolated and para-aminosalicylic acid was discovered. After that, mainly between the 1970s and 1980s, a series of chemotherapy agents used in multicenter trials were discovered or utilized to manage TB, which seemed to overcome the TB health problem [2]. No new first-line drug has been developed since rifampin in 1967 [3]. The global HIV pandemic has driven a rise in TB incidence [4]. Globally, 48% of notified TB patients had a documented positive HIV test result in 2013, and this value was higher in the African Region (76%) [5]. Among the 41 countries with the highest TB/HIV burden, 16 achieved levels of HIV positive tests ‡ 90%. HIV-TB comorbidity is also relevant problem in children. Schaff et al. reviewed the TB cases in a Cape Town hospital and reported that 22.3% of children were HIV-infected, concluding that young and/or HIV-infected children carried the brunt of the TB disease burden [6]. Poor adherence to a long TB therapeutic regimen, intermittent drug use, errors in medical prescriptions, low quality of TB drugs and ineffective TB control have led to the emergence of resistant TB [7,8]. Moreover, cellular mechanisms (i.e., lack of 10.1517/14656566.2015.1080240 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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TB is considered one of the most important epidemiological issues worldwide, and the global HIV pandemic has driven a rise in TB incidence. Poor adherence to long-term TB therapy, intermittent drug use, errors in medical prescriptions, low quality of old TB drugs and ineffective TB control have led to the emergence of resistant TB. Bedaquiline and delamanid seem to be very promising new anti-TB drugs for patients with MDR- or XDR-TB as part of a combination regimen. Specific studies performed in the pediatric population are needed to confirm pharmacokinetic and pharmacodynamic data of bedaquiline and delamanid in the first years of life as well as their safety and efficacy. Currently, bedaquiline and delamanid may be used on a case-by-case basis in children only when an effective treatment regimen cannot otherwise be provided. Data on the long duration of bedaquiline and delamanid treatment, including the potential interactions with other drugs included in anti-TB regimens or administered for an underlying comorbidity, are needed. Studies on bedaquiline and delamanid should also include pharmacokinetic--pharmacodynamic relationships for safety and efficacy, evaluation of adherence and palatability, development of resistance during treatment, drug penetration in cerebrospinal fluid in tuberculous meningitis and data on children as well as on population with comorbidities are urgently needed.

2.

Bedaquiline

Bedaquiline, the diarylquinoline TMC207, is synthesized in five steps from 3-phenylpropionic acid and parabromoaniline [30]. It is the only drug that targets the energy metabolism of mycobacteria [31,32]. ATP is an essential molecule for the survival of mycobacteria, and ATP production by ATP synthase is essential regardless of the nature of mycobacteria: active or dormant, replicating or non-replicating, extracellular or intracellular and fermenting or non-fermenting [33]. Bedaquiline is a selective inhibitor of the mycobacterial ATP synthase complex [31]. Pharmacokinetics and pharmacodynamics Bedaquiline binds ATP synthase at a defined binding site. Its affinity for the target decreases with increasing ionic strength. In the study by Haagsma et al., the results provide experimental support for the predicted function of bedaquiline in mimicking key residues in the proton transfer chain and blocking rotary movement of subunit C during catalysis [34]. Furthermore, the high affinity of bedaquiline at low proton motive force and low pH values may in part explain the exceptional ability of this compound to efficiently kill mycobacteria in different microenvironments [34]. The stereogenic center configuration of this drug plays an important role in its activity. In the initial phase, bedaquiline induces bacteriostasis on M. tuberculosis, remodeling ATPconsuming and ATP-producing pathways, which may enable the maintenance of ATP levels sufficient for bacterial viability for several days and thus prevent killing [35]. The utilization of the glycolytic pathway may contribute sufficient ATP for short-term survival, but upon continued inhibition of ATP synthase, this alternative pathway is apparently not sufficient. Second, bedaquiline displays a bactericidal mechanism [36]. Moreover, Berney et al. reported that the capacity of bedaquiline for killing M. tuberculosis through the inhibition of ATP synthase is relatively slow when compared to other frontline TB drugs, and that it has a bacteriostatic role for 4--7 days [37]. Bedaquiline is well absorbed following a single oral dose when administered under fed conditions [38,39]. The median time to reach the maximum plasma concentration (tmax) was found at 5 h post-dose. The PKs of TMC207 were 2.1

This box summarizes key points contained in the article.

mismatch repair, microsatellites, existence of drug resistanceconferring mutations, mistranslations, error-prone DNA polymerases) and external factors (i.e., antibiotics, anti-retroviral drugs, host-environment, smoking, co-morbidities including malnutrition and poverty) could contribute in a multifactorial manner to the genesis of resistant Mycobacterium tuberculosis [9-11]. Multidrug-resistant TB (MDR-TB) is caused by M. tuberculosis, which is resistant to at least the two most effective first-line medications: rifampin and isoniazid [12-14]. Extensively drug-resistant TB (XDR-TB) is defined as TB caused by a strain that is resistant to rifampin, isoniazid and also to at least one fluoroquinolone (levofloxacin and/or moxifloxacin) as well as any of the second-line injectable drugs such as capreomycin, kanamycin or amikacin [12-14]. Since 2006, when the first report on XDR-TB was published, more than 90 countries have reported the presence of at least one case of XDR-TB. Finally, the term ‘totally drug-resistant TB’ was proposed to define TB cases with a resistance profile beyond XDR-TB, in which the strain is virtually resistant to all available first- and second-line drugs [15-17]. MDR-TB poses problems for the global control of TB. Using second-line treatment regimens, the overall cure rate is ~ 60% for MDR-TB and 40% for XDR-TB [18-22]. Thus, there is a pressing need to develop new anti-TB drugs, which could have the following advantages: to shorten 2

and simplify the treatment of drug-susceptible TB; to provide shorter, safer, more effective and cheaper treatment alternatives for MDR-TB and XDR-TB; to abolish obstacles of the effective treatment of TB in HIV-positive individuals; and to shorten treatment of latent tuberculous infection (LTBI) [23-25]. In the last decade, in contrast with the previous 30 years, the development of new TB drugs has been widespread [26-29]. In this context, two main new drugs have gained importance and appear very promising: bedaquiline and delamanid. This review summarizes the main characteristics of these two drugs and their role in TB management.

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Bedaquiline and delamanid

comparable between healthy subjects and subjects with pulmonary TB [38,39]. Bedaquiline undergoes oxidative metabolism via the CYP3A4 enzyme and produces an active but comparatively less efficacious N-desmethyl metabolite (M2), which is further metabolized into M3 and M4 (N-demethylation) [31]. It follows a triphasic elimination and is characterized by an outstandingly long terminal half-life (~ 173 h) in humans. This is very important, as this may allow for intermittent drug administration when combined with others drugs in the regimen against MDR-TB and XDR-TB [38]. The half-life of M2 is comparatively higher than that of bedaquiline (~ 230 h) [39]. In a study conducted by Diacon et al., the authors reported the moderate absorption of bedaquiline, with a median time to reach maximum plasma concentration of 5--6 h and proportionally increasing concentrations in parallel with the dose level administered [40]. Additionally, Rustomjee et al. demonstrated in the treatment of 75 naı¨ve patients that bedaquiline PKs are linear across the dose range [41]. Administration of bedaquiline with food increased the relative bioavailability (95%) compared to administration without food. Bedaquiline and its M2 metabolite highly bind plasma protein (>99.9% for bedaquiline and similar for M2): small changes in plasma protein levels have a direct influence on the unbound fraction of both compounds, which itself directly impacts the pharmacokinetic (PK) properties [42]. The plasma proteins that bedaquiline and M2 bind to are yet unknown, but plasma albumin, being the most abundant plasma protein, is likely to be involved [42]. In TB patients, plasma albumin levels are generally decreased, and this fact results in a larger fraction of unbound drug, hence the higher clearance and volume of distribution at lower plasma concentrations [43]. The covariate of age was not found to influence the PK parameters of bedaquiline. Potential mechanism of resistance M. tuberculosis can potentially develop resistance against bedaquiline, which could be due to two important point mutations occurring in the atpE gene [44-46]. The mutations result in the prevention of bedaquiline from interfering with the passage of proton ions; hence, ATP synthesis cannot be blocked [45]. The acquisition of resistance to bedaquiline is inversely related to plasma concentration and treatment duration. However, in clinical trials, subjects achieved sputum conversion rapidly, which resulted in lower bacterial sputum load, preventing the development of resistance [47]. Hartkoorn et al. identified a possible mechanism of M. tuberculosis resistance to bedaquiline: the same mechanism through which the bacteria become resistant to clofazimine, another drug used against MDR-TB [48]. M. tuberculosis can develop resistance to these compounds when there is a mutation in the gene which codes for Mmpl5, a protein involved in 2.2

the export of siderophores (mycobactins and carboxymycobactins), essential for the bacterial acquisition of iron [48]. Drug efflux is another important resistance mechanism in M. tuberculosis: Gupta et al. demonstrated that the concomitant use of an efflux inhibitor, such as verapamil, profoundly decreases (by 8--16-fold) the MIC of bedaquiline to M. tuberculosis, leading to a major susceptibility of the bacteria to this drug [49]. Drugs interactions During a Phase I PK drug interaction trial in 37 healthy volunteers (aged 18 -- 65 years) with negative HIV antibodies and normal QT (A5267 study), the effects of efavirenz (a non-nucleoside reverse transcriptase inhibitor) on bedaquiline were evaluated, reporting an unlikely clinically significant interaction between the two drugs [50,51]. It must be noted that data concerning the interaction between bedaquiline and antiretroviral therapy are limited, and the majority have been derived from studies conducted on healthy volunteers [50,51]. The interactions between bedaquiline and other secondline drugs have not been completely exposed. A study with rifampin (a CYP3A4 inducer) showed that exposure (AUC336 h) to bedaquiline and M2 was significantly reduced (by 52 and 25%, respectively). A study with a combination of isoniazid/pyrazinamide showed a reduction in the exposure to bedaquiline (-13%) after 5 days of co-administration, while exposure to M2 increased (+30%). Bedaquiline increased exposure to both isoniazid and pyrazinamide. Moreover, the administration of bedaquiline in association with clofazimine and moxifloxacin may increase the risk of cardiotoxicity [52]. Thus, it is wise to monitor patients for cardiac dysrhythmia or QT prolongation, liver dysfunction and renal impairment. According to the World Health Organization interim policy guidance, caution should be exercised when administering bedaquiline together with drugs acting on the enzyme CYP3A4 that may inhibit liver function (i.e., ketoconazole and lopinavir/ritonavir) because they could increase bedaquiline concentrations, resulting in toxicity or inducing liver function (i.e., rifampin), as the co-administration could result in subtherapeutic bedaquiline concentrations with reduced efficacy [52]. Svensson et al. reported an increased clearance of bedaquiline when co-administered with rifampin and rifapentine [42]. Thus, the association between rifampin, in general, and bedaquiline is in general not recommended. Studies on rifabutin are ongoing [53]. 2.3

Adverse effects In the pooled group of subjects treated with bedaquiline alone, AEs were reported in 60.3% of subjects and most frequently related to the system organ classes of nervous system (24.3%) and gastrointestinal disorders (16.9%) [54]. Within these classes, the most frequent AE was headache (18.0%). Nausea, arthralgia, hemoptysis, chest pain, anorexia 2.4

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and rash are other common side effects (in order of descending frequency) reported during the therapy with bedaquiline [54]. This drug can also influence the elevation of hepatic transaminases [54]. The most important side effect that must be taken into particular account is QT prolongation [54]. In vitro studies have proven that cellular phospholipidosis induction, which is stronger in M2 than in bedaquiline, is responsible for the development of adverse effects such as QT prolongation, hepatotoxicity and myopathy [50]. However, the concentrations of M2 and bedaquiline obtained in in vivo studies did not produce such adverse effects, even at the maximum clearance level [50]. Diacon et al. reported adverse events, such as nausea, arthralgia, vomiting, headache, hyperuricemia and hemoptysis, which were of mild-to-moderate severity [55]. They also underlined a significant QT increase in bedaquiline-treated patients, which was completely reversible within 60 weeks of the end of the treatment [55]. In their case reports, Tiberi et al. reported anorexia and depression in one patient and generalized anxiety, deafness and diarrhea in the other patient, symptoms which have not prevented therapy continuation [56]. Importantly, Trial 208 reported 10 deaths in the bedaquiline groups, compared with 2 deaths in the control group. Although these events have not been directly linked to the new drugs, this information must not be ignored [57,58]. During the entire clinical development program of bedaquiline, 30 deaths were recorded in the treated groups compared to 6 in the placebo groups [59]. For this reason, the US FDA has placed a black box warning on bedaquiline, cautioning its use due to the significantly increased rates of unexplained death [60]. Approval On 28 December 2012, the FDA granted accelerated approval of Janssen/Johnson and Johnson’s drug bedaquiline fumarate to treat MDR-TB when an effective treatment regimen cannot otherwise be provided [61,62]. Bedaquiline was approved for adults aged >18 years and only as a part of combination therapy. It has undergone the accelerated approval program, as is the case in treatments of serious or life-threatening illnesses [59,63,64]. With the FDA approval of bedaquiline, the first TB drug with a novel target in 40 years, and with other additional drugs poised for clinical development, we finally have the prospect of new tools to tackle the epidemic of TB [60]. Bedaquiline also received marketing authorization in Russia on October 22, 2013. Conditional Marketing Authorization in the European Union (EU) was granted on March 5, 2014, and bedaquiline was approved in Korea on March 21, 2014. Bedaquiline is marketed under the trade name SIRTURO. It is now available in 100 mg tablets for oral administration, concomitant with food, which enhances its biodisponibility 2.5

4

[61]. The dosage recommended for adults is 400 mg once daily orally for the first two weeks followed by 200 mg three times every week with intakes at least 2 days (48 h) apart for 22 weeks. Bedaquiline should always be prescribed with a background regimen that includes three potentially active drugs. PK studies are ongoing in the pediatric population in order to define the optimal bedaquiline dose.

2.6

Performed clinical trials

Table 1 summarizes the available clinical trials on bedaquiline.

No data on the pediatric population are available at this time. Diacon et al. performed a two-center, double-blind, centrally randomized Phase II trial to investigate the early bactericidal activity (EBA), safety, tolerability and PKs of bedaquiline administered in 68 patients at different daily doses: 100, 200, 300 and 400 mg from treatment days 3--14, preceded by single daily loading doses of 200, 400, 500 and 700 mg, respectively, on treatment day 1 and 100, 300, 400 and 500 mg, respectively, on treatment day 2 [40]. The authors concluded that any dose of bedaquiline was continued until the end of the 14-day study period, suggesting that the highest of these doses compatible with safety considerations should further analyzed in future long-term clinical studies. Moreover, bedaquiline plasma concentrations and bactericidal activity appeared to increase with doses up to 400 mg daily; these data are in agreement with findings obtained by Rouan et al. [39,40]. Diacon et al. coordinated a Phase IIb, randomized, multicenter (trial sites were located in Brazil, India, Latvia, Peru, the Philippines, Russia, South Africa and Thailand), double-blind, placebo-controlled study (C208 stage 2), in which 160 adult patients (aged 18--65 years) received either bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks) or placebo plus a preferred five-drug, second-line anti-tuberculous background regimen [55]. The authors reported a statistically significant reduction in the time of sputum--culture conversion (p < 0.001), which was shorter in the bedaquiline group, and in the percentage of sputum conversion, which was higher in the bedaquiline group at 24 and 120 weeks (p = 0.008 and p = 0.04, respectively) [55]. Similar data have been reported by the same authors in a previously conducted study (C208 stage 1) with a small sample size (47 patients) and a short therapy duration (8 weeks) [65]. Tiberi et al. described the first experience of compassionate bedaquiline use in two MDR/XDR-TB patients (a 35-yearold Ukraine female and a 65-year-old Italian male). These subjects had radiological and clinical improvement as well as negative cultures after 180 days of bedaquiline associated with other TB therapies [56]. Halsema et al. reported a 28-year-old, HIV-negative Indian female with no prior history of TB treatment or contact, who was diagnosed with XDR-TB through screening on arrival in the UK; early treatment with bedaquiline added to the TB-background regimen was successful [66].

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Non-comparative, single-arm, open-label trial (C209 study)

233

Bedaquiline 400 mg once daily for 2 weeks and 200 mg three times weekly + background regimen

Diacon et al. (2014) [55]

Recently, a non-comparative, single-arm, open-label trial (C209) assessed the efficacy of bedaquiline in patients with MDR-TB with varying degrees of additional resistance who failed in previous therapies: the median time to sputum culture conversion was 57 days and consistent with both C208 stage 1 and stage 2 results [59,67,68]. Notably, although it was not a human trial, the murine study of Veziris et al. suggested the reduction of the duration of the second-line regimen containing bedaquiline from 18--24 to 12 months [69]. 3.

Delamanid

The second promising anti-TB drug is delamanid. Delamanid (Deltyba, OPC 67683) is a nitro-dihydro-imidazooxazole derivative with mycobacteria-specific antibacterial activity in vitro, without activity against Gram-positive or Gramnegative bacteria or intestinal flora [70]. The nitroimidazopyran derivative acts through the inhibition of the mycolic acid biosynthesis, thus preventing the formation of the mycobacterial cell envelope and secondly, facilitating better drug penetration [70]. Delamanid belongs to the nitroimidazoles, a class of compounds widely clinically used for the management of anaerobic bacterial infections. While metronidazole has activity only against anaerobically adapted M. tuberculosis, bicyclic nitroimidazoles show both aerobic and anaerobic activity against M. tuberculosis [71]. These compounds have low water solubility, a characteristic which can affect the thermodynamic stability of particular crystalline polymorphs. For this reason, delamanid requires formulation in 5% gum Arabic [71]. Mycobacteria are well known to be wax-rich bacteria, and a main component of the wax is mycolic acid, which is detected only in mycobacteria and not in Gram-positive or Gramnegative bacteria or in mammalian cells [72]. Genome research of tubercle bacilli has verified this lipid richness, indicating that there are almost 250 distinct enzymes involved in the lipid metabolism of tubercle bacilli [72]. Matsumoto et al. observed the intracellular killing activity of different compounds, and they concluded that delamanid demonstrated the most potent killing activity, similar to that of rifampicin and superior to that of isoniazid [73]. Delamanid demonstrated potent in vitro killing ability even at short exposure times, giving rise to the hypothesis that the use of this compound in TB shortened the overall duration of treatment. The authors concluded that the qualities of delamanid, such as shortened treatment duration, effectiveness against MDRTB, the ability to be used safely in HIV/AIDS patients, and in the treatment of LTBI, could help to address the unmet needs of TB chemotherapy [73]. Pharmacokinetics and pharmacodynamics Delamanid is a pro-drug, which is activated by the M. tuberculosis enzyme deazaflavin-dependent nitroreductase (Rv3547) [74]. Experimentally isolated delamanid-resistant 3.1

CDC [59]

160

18 -- 65

18 -- 65

24 months + 2 years of follow-up

Statistically significant (p < 0.001) reduction in the time of sputum--culture conversion and in the percentage of sputum conversion at 24 and 120 weeks (p = 0.008 and p = 0.04, respectively) in the bedaquiline group Time of sputum conversion at 57 days 24 weeks

Bedaquiline was superior to placebo in inducing sputum conversion (p = 0.003) 8 weeks

Bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg three times a week for 6 weeks), or placebo, plus background regimen Bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg three times a week for 6 weeks), or placebo, plus background regimen 18 -- 65 47

Phase IIb, randomized, multicenter, double-blind, placebocontrolled study (C208 Stage 1) Phase IIb, randomized, multicenter, double-blind, placebocontrolled study (C208 Stage 2) Diacon et al. (2009) [65]

Type of therapy Age of patients (years) No. of patients Type of study Authors (year)

Table 1. Principal published studies on bedaquiline.

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Therapy duration

Comment

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mycobacteria did not metabolize the compound, and a mutation in the M. tuberculosis Rv3547 gene (responsible for activating PA-824) among the resistant organisms suggests that this enzyme is involved in activating delamanid [74]. A reactive intermediate metabolite, formed between delamanid and desnitro-imidazooxazole derivative, seems to play a vital role in the inhibition of mycolic acid production [75]. Delamanid has bactericidal action against M. tuberculosis [76]. Diacon et al. performed a Phase IIa, open-label, active controlled randomized clinical trial to evaluate the safety, efficacy and PKs of four dosages (100, 200, 300 and 400 mg) of delamanid, orally administered once daily for 14 consecutive days, compared with the standard four-drug anti-TB treatment (isoniazid + rifampin + pyrazinamide + ethambutol) in 54 patients aged 18--64 years old with newly diagnosed smear-positive pulmonary TB [77]. The authors showed that delamanid exposure did not increase in a dose-proportional fashion, and the EBA was not related to dosage [78,79]. Nevertheless, a moderate but significant correlation between drug exposure and EBA at 0--14 days was observed, demonstrating a significant exposure--EBA relationship throughout the 14 days. The bactericidal activity of delamanid reached significance on day 3 and thereafter continued at a magnitude similar to that of the currently recommended four-drug combination. Although a greater proportion of patients in the 200 and 300 mg treatment arms achieved a better treatment response (in terms of sputum decline) compared to the 100 mg treatment arm, plasma exposure of delamanid was not proportional to dose and plateaued at 300 mg. These results can be explained by considering the nature of delamanid, which is poorly soluble in water, and the solution saturation can therefore limit absorption at higher dosages [77]. Administration of delamanid with food increased the relative bioavailability (95%) compared to administration without food [77]. The complete metabolic profile of delamanid has not yet been determined. Delamanid and its metabolites highly bind plasma proteins, especially albumin and thus it has a large volume of distribution [80,81]. Delamanid is rapidly metabolized to DM-6705 due to a reaction between the amino acid groups in albumin and the 5-C of 6-nitro2,3-dihydro-imidazo (2,1--b) oxazole moiety of delamanid, while a minimal quantity is metabolized in human liver microsomes by CYP450 3A4. Metabolite DM-6705 is probably metabolized via hydrolysis to DM-6704 and DM-6706 and via CYP3A4 oxidation to DM-6720. CYP3A4 also facilitates the further biotransformation of DM-6704 and DM-6720 into their final forms, DM-6717 and DM-6718, respectively [80]. Because NADPH-dependent metabolites were hardly detected in the incubation mixture, it seems that delamanid is not metabolized by CYP enzymes. However, after oral administration of delamanid to humans and animals, at least four metabolites (M1, M2, M3 and M4) were detected and identified in the plasma [82]. Delamanid is considered to be 6

primarily metabolized to the (R)-2-amino-4,5-dihydrooxazole derivative (M1). The primary metabolite, M1, is proposed to undergo subsequent biotransformation reactions, including oxidation to (4RS,5S)-2-amino-4,5-dihydro-4-hydroxyoxazole derivative (M2) and M2 to (S)-2-imino-oxazolidin4-one derivative (M3). M1 is further proposed to be metabolized to a (R)-4,5-dihydro-2-oxooxazole derivative (M4) [82]. Matsumoto et al. have previously demonstrated the absence of delamanid inhibition on CYP enzymes [73]. Simokawa et al. reported that the inhibitory effects of delamanid’s metabolites were observed only at metabolite concentrations exceeding those observed in human plasma during clinical trials, showing no inhibitory effects on eight CYP isoforms [82]. The plasma half-life (t1/2) of delamanid is 30--38 h, and the t1/2 of its metabolites ranges from 122 to 322 h [83]. In case of hypoalbuminemia, delamanid clearance is higher than normal. Finally, the elimination of delamanid occurs mainly via the feces: in fact, it is not excreted in urine [83]. Potential mechanism of resistance A mutation in one of the five coenzyme F420 genes (fgd, Rv3547, fbiA, fbiB and fbiC) has been proposed as a mechanism of resistance against delamanid in mycobacteria [80,81]. In vitro, resistance could be developed through the lack of delamanid conversion into its active form, while in vivo it could be observed in patients treated in association with few anti-TB drugs or with ineffective anti-TB drugs. Nevertheless, cross-resistance between delamanid and rifampin, isoniazid, ethambutol or streptomycin has not been observed [80,81]. 3.2

Drugs interactions In vitro studies have shown that delamanid is neither metabolized by CYP450 enzymes nor influences the enzymes at the expected therapeutic concentrations [73,75]. Data reported by Simokawa et al. suggests that delamanid and its metabolites have no inhibitory effects on CYP enzymes at human therapeutic concentrations, and therefore it is unlikely to be a clinically relevant CYP-mediated drug interaction [82]. 3.3

Adverse effects The most relevant AE revealed by Gler et al. was a prolonged QT interval, which was not associated with clinical manifestations such as syncope or arrhythmia [84]. The frequency was relevant, as it was registered in 13.1% of patients treated with 200 mg delamanid twice daily compared to the 9.9% in the 100 mg twice daily group and to the 3.8% in the placebo group. A concomitant condition that could exacerbate QT-interval prolongation is hypokalemia, which is often associated with the use of injectable anti-TB drugs [85]. Evidence suggests that QT-interval prolongation is closely correlated to levels of the major delamanid metabolite (DM-6705), the formation and metabolism of which are regulated by plasma albumin and CYP3A, respectively. This fact calls to attention those patients who are, for different reasons, 3.4

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hypoalbuminemic [81]. Due to this risk of QT-interval prolongation, delamanid could not be administered with bedaquiline. Another adverse cardiac event reported in Gler’s trial was palpitation [84]. Notably, this symptom, which occurred with mild severity for the majority, was reported in both placebo and delamanid groups and in patients who had a pre-existing condition that could cause this symptoms. In addition, it lasted only for the first months of therapy (1--62 days) [84,85]. Gler et al. also reported other adverse effects of delamanid, but all of these were mild or moderate events with spontaneous resolution such as nausea, vomiting, insomnia and upper abdominal pain [84]. The relevant aspect is that no new clinically significant adverse events were observed when delamanid treatment was prolonged [83,86]. Approval In 2014, delamanid received its first global approval by the European Medicines Agency for use in combination with the standard anti-tuberculous regimen in patients with MDR-TB [87,88]. The Committee for Medicinal Products for Human Use of the European Medicines Agency initially failed to recommend marketing approval for delamanid in MDR-TB, as the clinical trials performed were too short, but on November 21, 2013, it gave conditional marketing authorization after having observed the results of trials 208 and 116 [89]. Delamanid is now available in 50 mg tablets for oral administration [75]. The dosage recommended for adults is 100 mg twice daily for 24 weeks. Delamanid should always be prescribed with a background regimen that includes potentially active drugs. PK studies are ongoing in the pediatric population in order to define the optimal delamanid dose.

demonstrated that favorable outcomes were significantly increased 74.5% in patients in the long term (‡6 months), compared with 55.0% in the short term (£2 months) (p = 0.001). Moreover, patient mortality was also greatly reduced following extended treatment with delamanid: only two (1.0%) deaths occurred in the long-term treatment group, while 19 (8.3%) occurred in the short-term treatment or non-delamanid groups (p = 0.001) [86,90]. To our knowledge, the only pediatric case reported on the use of delamanid is the one published by our group [91]. We reported the case of a 12-year-old Italian boy with laryngeal and pulmonary XDR-TB successfully treated with the compassionate use of delamanid, after having consulted the TB Consilium platform [91]. At the time of writing, this patient is continuing intensive TB therapy, including delamanid 100 mg twice daily for 15 months; he is doing well and was able to return to his community and to restart a ‘normal’ life.

3.5

4.

As highlighted here, bedaquiline and delamanid seem to be very promising new anti-TB drugs. The potential cardiologic side effects and the reportedly linked mysterious deaths raise some concern, but the context in which these drugs would be considered is so severe that it is probably ethically worthwhile to use them. However, specific studies performed in the pediatric population are needed to confirm the PK and pharmacodynamic data in the first years of life as well as their safety and efficacy. This seems particularly important, considering the long duration of TB treatment required for MDRand XDR-TB as well as the potential interactions with other drugs included in anti-TB regimens or administered for an underlying comorbidity. 5.

3.6

Conclusion

Expert opinion

Performed clinical trials

Table 2 summarizes the available studies on delamanid.

The first clinical trial on delamanid was the one conducted by Gler et al. It was a multicenter, double-blind, stratified, randomized, placebo-controlled trial (242--07--204, Phase II) that took place across nine countries (Philippines, Peru, Latvia, Estonia, China, Japan, Korea, Egypt and the US) and involved 481 sputum culture-positive MDR-TB patients (aged 16--64 years), who received an 8-week delamanid treatment of 100 or 200 mg twice a day or placebo in combination with a standard TB therapy during hospitalization [84]. The authors concluded that a statistically significant difference in sputum--culture conversion between the delamanid group and the placebo group occurred (p = 0.001) [84]. The other historical delamanid study was performed by Skripconokar et al. [86]. It was composed of a trial (trial 242-07-208) and an observational study (study 116), both derived from the previously performed trial 204 and sponsored by Otsuka Pharmaceutical Development and Commercialization (Otsuka, Tokyo, Japan). These studies

Bedaquiline and delamanid seem to satisfy the needs of new anti-TB drugs that are effective on MDR and XDR strains, provide an easy route of administration, have rare side effects, and possibly reduce therapy duration. However, few clinical data on these drugs are available. Some studies on bedaquiline have already been completed and are ongoing, but only in adults [92]. Currently, therefore, bedaquiline may be used on a case-by-case basis in children only when an effective treatment regimen cannot otherwise be provided [59]. A Phase II, open-label, multicenter study, which has not yet begun, plans to involve young subjects (0--18 years old) with confirmed or probable pulmonary MDR-TB to assess the PKs of bedaquiline in combination with a background regimen. The study will consist of a screening phase, a 24 week open-label treatment phase during which all participants will receive bedaquiline plus background regimen medications, and a 96-week follow-up phase. There will be four age-based cohorts in this study: cohort 1, from ‡ 12 to < 18 years of age; cohort 2,

Expert Opin. Pharmacother. (2015) 16(15)

7

8

24 months

213

421

Non-controlled, open-label trial

Multicenter, observational

Skripconoka et al. (2013) [90]

16 -- 48

Delamanid 200 mg or 200 mg twice a day + standard anti-TB therapy Delamanid 200 mg or 200 mg twice a day + standard anti-TB therapy 16 -- 64

6 months

Statistically significant difference in sputum--culture conversion between delamanid group and placebo group Favorable outcomes significantly increased in long term (‡6 months) treatment group (p = 0.001). Patient mortality greatly reduced in the extended treatment with delamanid (p = 0.001) 2 months Delamanid 200 mg twice a day versus placebo + standard anti-TB therapy 16 -- 64 481 Double-blind, multicenter, randomized, placebocontrolled Phase II trial Gler et al. (2015) [88]

No. of patients Type of study Authors (year)

Table 2. Principal published studies available on delamanid.

Age of patients (years)

Type of therapy

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Therapy duration

Comment

S. Esposito et al.

from ‡ 5 to < 12 years of age; cohort 3, from ‡ 2 to < 5 years of age; and cohort 4, from 0 months to < 2 years of age. Participants in these cohorts will be enrolled sequentially, beginning with the oldest age cohort [93]. The primary objectives are to assess the safety and tolerability as well as the PKs of bedaquiline over a 24-week treatment period in the different age cohorts. Further studies are needed to additionally clarify these objectives in patients with comorbidities, including HIV, especially considering treatment with other concomitant drugs. Interestingly, based on its efficacy in the animal model, bedaquiline has been proposed for the treatment of LTBI of close contacts of MDR- and XDR-TB cases [94]. As only few studies have analyzed the usefulness of treatment in the contacts of patients with MDR- and XDRTB (particularly in the pediatric population), further evidence concerning the efficacy and safety of bedaquiline as treatment strategy should be collected before considering its routine use for LTBI. The situation is similar for delamanid. Studies of the longterm evaluation of delamanid safety as well as its efficacy and safety in HIV-infected patients are ongoing in adults. In the pediatric population, there are two ongoing Otsuka Pharmaceutical-sponsored pediatric clinical trials with delamanid [95,96]. The first one is a Phase I, open-label study involving MDR-TB children and adolescents: children aged 6--11 years old who are treated with delamanid 50 mg twice daily and 12--17-year-old adolescents who are treated with 100 mg twice daily. The study is comparing their plasma concentrations to those achieved in adults [95]. The second, which is a Phase II clinical trial, is assessing the efficacy, safety and PK profile of delamanid in addition to the standard TB regimen in children and adolescents aged ‡ 6--18 years, but the amendment of the protocol to include younger children and infants (aged 3--5 years and 0--2 years) is planned when a pediatric formulation of delamanid becomes available [96]. No data on delamanid for the treatment of LTBI is available. Apart from bedaquiline and delamanid, pretomanid is another new and promising drug that is emerging [97]. The combination of pretomanid, moxifloxacin, and pyrazinamide was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible TB during 8 weeks of treatment [98]. Results were consistent between drug-susceptible and MDR-TB. This new regimen is ready to enter Phase III trials in patients with drug-susceptible TB and MDR-TB, with the goal of shortening and simplifying treatment. In conclusion, the emerging relevance of MDR- and XDRTB in the pediatric population is the reason for performing adequate studies on these new drugs. Studies on bedaquiline and delamanid should include not only safety, tolerability and PKs in the short- and long-term but should also consider PK--pharmacodynamic relationships for safety and efficacy, evaluation of adherence and palatability, development of resistance during treatment and drug penetration in cerebrospinal fluid in tuberculous meningitis. In addition, for both bedaquiline and delamanid future studies should focus on

Expert Opin. Pharmacother. (2015) 16(15)

Bedaquiline and delamanid

children defining the optimal dose in the first years of life, on the efficacy of these drugs associated with different background regimens, on their use in HIV-infected patients as well as in patients with other comorbidities considering the clinical impact of interference with the other drugs received for the underlying disease, on the possibility to administer them for more than 24 weeks due to the complexity of MDR- and XDR-TB cases, and on their role in treatment of LTBI. In addition, the possibility to administer at the same time bedaquiline and delamanid should be evaluated in order to analyze whether these two drugs administered Bibliography

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Affiliation

Susanna Esposito†1, Sonia Bianchini1 & Francesco Blasi2 † Author for correspondence 1 Universit
a degli Studi di Milano, Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy Tel: +39 02 55 03 24 98; Fax: +39 02 50 32 02 06; E-mail: [email protected] 2 Universit
a degli Studi di Milano, Pneumology Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy