Journal of Pharmacology and Pharmacotherapeutics

MOLECULES OF THE MILLENNIUM
Year
: 2014  |  Volume : 5  |  Issue : 3  |  Page : 222--224

Delamanid: A new armor in combating drug-resistant tuberculosis


Alphienes Stanley Xavier, Mageshwaran Lakshmanan 
 Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India

Correspondence Address:
Alphienes Stanley Xavier
Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry - 605 006
India

Abstract

Intense search has been made in the discovery of newer anti-TB drugs to tackle the issues such as drug resistance, HIV co-infection and risk of drug-drug interactions in the management of TB. Delamanid, a newer mycobacterial cell wall synthesis inhibitor, received a conditional approval from European medicines agency (EMA) for the treatment of MDR-TB. Preclinical and clinical studies have shown that delamanid has high potency, least risk for drug-drug interactions and better tolerability.



How to cite this article:
Xavier AS, Lakshmanan M. Delamanid: A new armor in combating drug-resistant tuberculosis.J Pharmacol Pharmacother 2014;5:222-224


How to cite this URL:
Xavier AS, Lakshmanan M. Delamanid: A new armor in combating drug-resistant tuberculosis. J Pharmacol Pharmacother [serial online] 2014 [cited 2020 May 28 ];5:222-224
Available from: http://www.jpharmacol.com/text.asp?2014/5/3/222/136121


Full Text

 Introduction



Multidrug-resistant tuberculosis (MDR-TB) is the development of resistance to rifampicin and isoniazid in Mycobacterium tuberculosis infection. If the resistance extends to second-line anti-TB drugs such as fluoroquinolones and an injectable drug, then it is called as extensively drug-resistant TB (XDR-TB). In India and other South Asian countries, totally drug-resistant TB has been often reported recently. [1] Treating these drug-resistant TB conditions is a challenging task because of longer duration of treatment, vulnerability to drug interactions, toxicity, and the burden caused by the cost of treatment. Moreover, co-existence of TB in immunosuppressed conditions such as AIDS and malnutrition, and increased incidence of MDR and XDR-TB in such situations are frequent. Hence, it is well speculated that these issues are the most important hindrances towards achieving TB-free society. Therefore, there is an unmet need to develop drugs acting via novel targets with better efficacy with least chance for drug interactions and a desirable toxicity profile. To combat these problems, newer targets and drugs against TB are being explored and many newer drugs are in the pipeline of development. The new drug delamanid received conditional approval by European Medicines Agency (EMA) for the treatment of MDR-TB in November 2013.

 Mechanism of Action



Delamanid is a dihydro-nitroimidazooxazole derivative. It acts by inhibiting the synthesis of mycobacterial cell wall components, methoxy mycolic acid and ketomycolic acid. Delamanid is a pro-drug which gets activated by the enzyme deazaflavin dependent nitroreductase (Rv3547). A reactive intermediate metabolite, formed between delamanid and desnitro-imidazooxazole derivative, is considered to play a vital role in the inhibition of mycolic acid production.

 Pharmacokinetics



It is advised to take delamanid along with food since the absorption gets better with food, in contrast to the first-line anti-TB drugs which should be taken on empty stomach. After oral administration, the maximum concentration is observed at 4-5 h. The half-life is 38 h after drug discontinuation. Steady-state concentration is reached after 10-14 days. [2] In early trials, delamanid exposure was not found to be proportional to the dosage and it plateaued at 300 mg. This might be due to the poor water solubility of the drug and the limited absorption at higher doses.

 Preclinical Studies



In in-vitro studies, delamanid showed more potent antibacterial activity against drug-susceptible and drug-resistant strains of M. tuberculosis. The minimum inhibitory concentration was observed in an extremely lower range of 0.006-0.024 μg/ml. Post antibiotic effect on intracellular organisms had been demonstrated after pulsed therapy, which was comparable with that of rifampicin. There was no cross-resistance and antagonist effect was observed with first-line anti-TB drugs. Delamanid was devoid of mutagenicity in bacterial reverse mutation test. High therapeutic efficacy with quicker eradication of tubercular bacilli was demonstrated in experimental mouse models. [3]

 Clinical Trials



Early bactericidal activity

Early bactericidal activity of different doses of delamanid was demonstrated in smear-positive TB patients (n = 48) by reduction in colony-forming units (CFU) of M. Tuberculosis. The treatment duration was 14 days. Increased reduction in CFU was observed with 200 mg/day and 300 mg/day doses. Delamanid showed monophasic bactericidal activity in contrast to rifampicin and isoniazid which showed biphasic activity. [2]

Short-term trial

In a 2-month randomized placebo-controlled clinical trial conducted on HIV-negative MDR-TB patients, delamanid was administered along with World Health Organization (WHO)-approved optimized background regimen (OBR). Higher sputum culture conversion rates were observed in the treatment group compared to patients on placebo and background regimen. [4]

Long-term trial

Long-term treatment with delamanid and a 24-month observational study was done as a continuation of previous short-term trial to find out the treatment outcome. Patients who received delamanid for ≥6 months had more favorable outcome than the patients who received ≤2 months of treatment. There was significant reduction in mortality in the long-term delamanid treated group. [5]

 Adverse Effects



The incidence of QT prolongation was observed to be significantly higher in the treatment group compared to the placebo group. This effect was observed to be dose dependent as it was seen frequently in 200 mg BD/day group than in 100 mg BD/day group. [4] However, it was of mild to moderate severity and not associated with symptoms of syncope and arrhythmia. No other serious treatment emergent adverse effects had been observed in the clinical trials.

 Drug Interactions



In vitro studies have shown that drug is neither metabolized by cytochrome P450 (CYP 450) enzymes nor influences the enzymes at the expected therapeutic concentrations. [3] In clinical trials conducted on healthy subjects, no significant interactions were observed between delamanid and anti-retroviral drugs such as tenofovir, lopinavir/ritonavir, and efavirenz. [6] This is a desired property, as other anti-TB drugs can be combined with delamanid without any fear of drug interactions.

 Current Status



EMA has issued a conditional marketing authorization for delamanid (Deltyba, 50 mg tablet). It should be used as a part of an appropriate combination regimen for pulmonary MDR-TB in adult patients in whom the current approved regimen cannot be used because of resistance or intolerability. [7]

 Advantages and Limitations



High potent action, least chance of drug-drug interactions, better toxicity profile, and post antibiotic effect against intracellular bacilli are the advantages with delamanid which will be helpful in reducing the treatment duration and risk of toxicity in MDR-TB. Long-term clinical trials on the safety and efficacy, interaction studies with standard and newer anti-TB agents, pharmacokinetic studies in special populations, and studies on drug administration with food need to be conducted in future.

 Conclusion



Recent approval of anti-TB drugs such as bedaquiline and delamanid has boosted our confidence in managing drug-resistant TB. The desirable properties of good efficacy, least toxicity, and absence of interaction with antiretroviral drugs might make delamanid an important option in treating MDR-TB, XDR-TB, and TB in HIV-positive individuals.

References

1Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2012;54:579-81.
2Diacon AH, Dawson R, Hanekom M, Narunsky K, Venter A, Hittel N, et al. Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients. Int J Tuberc Lung Dis 2011;15:949-54.
3Matsumoto M, Hashizume H, Tomishige T, Kawasaki M, Tsubouchi H, Sasaki H, et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med 2006;3:e466.
4Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med 2012;366:2151-60.
5Skripconoka V, Danilovits M, Pehme L, Tomson T, Skenders G, Kummik T, et al. Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J 2013;41:1393-400.
6International AIDS Society. Available from: http://www.iasociety.org/Abstracts/A200747433.aspx. [Last accessed on 2014 Jan 16].
7European Medicines Agency-Human medicines-Deltyba. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002552/WC500155458.pdf. [Last accessed on 2014 Jan 16].