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New molecular entity: Late last year FDA approved bedaquiline tablets for the treatment of pulmonary multi-drug-resistant tuberculosis (MDR-TB).
A diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multidrug-resistant TB.
Late last year FDA approved bedaquiline (Sirturo, Janssen Therapeutics) tablets for the treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB) as part of combination therapy in adults. The accelerated approval was based on the end point of time to sputum culture conversion compared with placebo. Bedaquiline, a diarylquinolone antimycobacterial drug, is recommended when other alternative treatments cannot be provided. It is not indicated for the treatment of latent, extra-pulmonary, or drug-sensitive TB.
In 2011 TB affected more than 10,000 patients in the United States and almost 9 million worldwide, according to the Centers for Disease Control and Prevention. TB is caused by Mycobacterium tuberculosis and commonly infects one’s lungs, but also may infect the brain, kidneys, and spine. MDR-TB is TB resistant to isoniazid and rifampin. Although only 98 cases occurred in 2011 in the United States, the World Health Organization estimates that MDR-TB will affect 2 million people from 2011 to 2015.
Bedaquiline is the first drug approved specifically for MDR-TB and is used in combination with other antimycobacterial agents. Bedaquiline carries a boxed warning about the risk of QT prolongation and an increased risk of death as seen in 1 placebo-controlled trial. It should only be used when an effective drug regimen is not available or cannot be provided.
Efficacy. FDA’s approval of bedaquiline was based on data from TMC207-C208 studies 1 and 2, with the primary end point being the time to sputum culture conversion. In study 1, a placebo-controlled, double-blind, randomized trial of newly diagnosed patients with MDR-TB, 79 patients received bedaquiline in combination with other drugs to treat MDR-TB and 81 received placebo and the combination of other drugs for MDR-TB, which included ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone or an available alternative. Bedaquiline was given at a dose of 400 mg once daily for the first 2 weeks of treatment and at a dose of 200 mg 3 times per week for another 22 weeks. After the 24-week treatment with bedaquiline, patients were continued on their other MDR-TB drugs for 18 to 24 months, or another 12 months following the first confirmed negative culture. At 24 weeks, culture conversion success was demonstrated in 77.6% of patients who received bedaquiline combination treatment versus 57.6% of patients in the placebo group (P=.014). At 72 weeks, culture conversion success was seen in 70.1% of the bedaquiline treatment group versus 56.1% of the placebo treatment group (P=.092). The median time to conversion was 83 days in the bedaquiline group compared with 125 days in the placebo group.
In study 2, a smaller placebo-controlled study, bedaquiline was administered for only 8 weeks instead of 24 weeks. The patients treated with bedaquiline (n=23) had greater success than the placebo group (n=24) in terms of decreased time to culture conversion and improved rates of culture conversion at week 8.
Safety. The most common adverse reactions that occurred in patients treated with bedaquiline during the clinical trials were nausea (38%), arthralgia (32.9%), headache (27.8%), hemoptysis (17.7%), and chest pain (11.4%). Bedaquiline exposure may be reduced if coadministered with CYP3A4 inducers or increased if coadministered with CYP3A4 inhibitors. The manufacturer recommends strong CYP3A4 inhibitors not be used for more than 14 consecutive days while on bedaquiline unless benefit outweighs the risks.
Bedaquiline carries a boxed warning of increased risk of death, observed during 1 of the clinical trials in comparison to the placebo arm (11.4% vs 2.5%). Therefore, the drug should only be used when other effective treatments are not provided. The warning also includes the risk of QT prolongation when administering bedaquiline and additional risk when used with drugs that prolong the QT interval. A baseline electrocardiogram should be obtained and repeated at 2, 12, and 24 weeks after therapy initiation.
Dosing. The recommended dosage of bedaquiline is 400 mg once daily with food for the first 2 weeks of treatment. Then from weeks 3 to 24, the dosage should be 200 mg 3 times per week with food with 48 hours between doses. If a patient misses a dose during the first 2 weeks of treatment, the dose should not be made up but the patient should continue the dosing schedule. At weeks 3 to 24, the missed doses should be taken as soon as possible and then the patient can resume the 3 times per week treatment regimen. Nonadherence to the treatment regimen could result in treatment failure or resistance. Therefore bedaquiline should be administered under direct observation. It should be administered in combination with at least 3 drugs that are active against the patient’s TB isolate.