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Multiple drug-resistant tuberculosis: Bedaquiline shows efficacy, but concern for hepatotoxicity

The treatment of drug sensitive strains of tuberculosis ( TB ) requires minimum duration of 6 months. However, for multiple drug-resistant tuberculosis ( MDR-TB ) and extensive drug-resistance tuberculosis ( XDR-TB ) the duration is more than 20 months.
MDR-TB and XDR-TB are more difficult to manage, cure rate with second line drugs is very less and relapse rate is very high.

This situation demands for the development of new anti-tubercular drugs with a different mechanism of action. Research in this area has fastened up in last 10 years after launch of the global plan to stop tuberculosis. Bedaquiline ( Sirturo ) has been developed recently.

Bedaquiline is the first compound from the new class diarylquinolines that acts by inhibiting bacterial adenosine triphosphate ( ATP ) synthetase enzyme. This compound has shown high activity against both sensitive as well as resistant strain of mycobacterium.
ATP synthetase is the essential enzyme for the production for energy in the all-living organisms. ATP synthetase enzyme consists of two complexes, hydrophilic F1 and membrane embedded F0. The hydrophobic side of Bedaquiline binds to c-subunit of the F0 complex and interferes with its rotatory movement leading to inadequate synthesis of ATP.
Bedaquiline specifically inhibits the mycobacterium ATP synthetase as compared to mitochondrial ATP synthetase.
Bedaquiline is well absorbed after oral ingestion and is metabolized by hepatic CYP450 enzymes to less active metabolite N-desmethyl M2. The average half-life over a dosing interval is about 24 hr. The terminal half-life of it is quite long approximately 173 hr.

The efficacy of Bedaquiline was assessed in newly diagnosed sputum positive patients. A total of 75 patients were randomized, they were given once daily either Bedaquiline ( 25,100 or 400 mg ) or 600 mg Rifampicin or 300 mg Isoniazid for 7 days.
Early bactericidal activity ( EBA ) of Bedaquiline was similar to Rifampicin and Isoniazid from 4 th day onwards onward at 400 mg dose.

Later efficacy of Bedaquiline was evaluated in a multicentric trial in adult patients with newly diagnosed smear positive pulmonary tuberculosis caused by MDR-TB strains.
A total of 47 patients was involved in 8 weeks trial. 23 patients were administrated Bedaquiline, initially daily dose of 400 mg for 2 weeks, followed by 200 mg three times a week for 6 weeks, in addition to background regimen of the second line drugs while 23 patients received placebo and background regimen.
The time for sputum conversion was shorter in Bedaquiline group as compared with the placebo group ( hazard ratio, HR=1.8; p = 0.003 ). After 8 weeks of therapy the conversion rates of sputum culture were 48% in the Bedaquiline group ( 10 of 21 patients ) and 9% in the placebo group ( 2 of 23 patients ).
After 8 weeks, these patients were given only background and were evaluated at 24 weeks; the rate of sputum conversion was more in Bedaquiline treated group significant ( hazard ratio, HR=2.25; P = 0.031 ).

The common adverse events seen with Bedaquiline in clinical trials were: nausea, diarrhea, bilateral hearing impairment, viral infections, pain, acne and non-cardiac chest pain.
Except for nausea, which occurred more frequently in Bedaquiline group as compared with the placebo group ( 26% vs 4%; P = 0.04 ), there was no statistically difference in incidence of other adverse events in both groups.
It was also found to increase QT interval, but no pathological increase in QT interval ( greater than 500 ms ) was seen.
A matter of concern is its hepatotoxicity, it was found to increase the level of transaminases. It was also found to increase the risk of death, 11.4% patients died in Bedaquilne arm as compared to 2.5% in the placebo arm.

As hepatic Cyp450 enzymes metabolize Bedaquiline, many drug interactions can occur because of microsomal enzyme induction and inhibition.
Rifampicin was found to decrease its plasma concentration to half. ( Xagena )

Goel D, J Pharmacol Pharmacother 2014;5:76-78