Bedaquiline Tablets (Sirturo™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA, Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved bedaquiline, a first in class drug for the treatment of multidrug-resistant tuberculosis. Bedaquiline, which was approved under the FDA’s accelerated approval process, is a diarylquinoline antimycobacterial that inhibits the enzyme that generates energy in Mycobacterium tuberculosis. It is manufactured by Kemwell Pvt. Ltd in India and marketed by Janssen Therapeutics as Sirturo.
Bedaquiline is indicated in combination with other antimycobacterial drugs for patients with multidrug-resistant pulmonary tuberculosis in adults (≥ 18 years of age).1 The drug should be reserved for use only when there are no other effective treatment regimens available. It should be given by directly observed therapy. This means that a trained health care worker or other designated individual (excluding a family member) provides the prescribed medication and watches the patient swallow every dose.
The recommended dose of bedaquiline for the first 2 weeks is 400 mg (4 × 100 mg) once daily with food. For weeks 3-24, the dose is 200 mg (2 × 100 mg) three times per week with food with at least 48 hours between doses. Bedaquiline is given in combination with at least three other drugs that the patient’s isolate has been shown to be susceptible to in vitro.1 If these data are not available, treatment should be initiated with at least four other drugs to which the patient’s isolate are likely to be susceptible. Dose adjustment is not required in patients with mild-to-moderate hepatic and renal dysfunction. Coadmistration with CYP3A4 inducers and strong inhibitors (e.g., rifampin, rifapentine) for more than 14 days should be avoided.
Bedaquiline is available as 100 mg tablets.
Bedaquiline provides a new and effective option for treating multidrug-resistant tuberculosis.
An increased risk of death has been associated with bedaquiline treatment compared to placebo (11.4% vs 2.5%).1 The drug prolongs QT interval. An ECG should be done before beginning treatment and no later than 2, 12, and 24 weeks thereafter. Serum electrolytes (sodium, potassium, calcium, and magnesium) should be assessed before treatment and adjusted if abnormal. Treatment should be discontinued if ventricular arrhythmia develops or if QTcF interval is > 500 ms.
Bedaquiline is a new drug that targets mycobacterial ATP synthase and is highly active on replicating as well as dormant bacteria.2,3 Its efficacy for the treatment of multidrug-resistant tuberculosis was evaluated in a randomized, double-blind, placebo-controlled study.1 Subjects were mainly males (63%), median age of 34 years, 35% black, 17.5% Hispanic, 12.5% white, 25.6% of other races, 15% were HIV-positive, and 62% had cavitations in one lung. They were randomized to bedaquiline plus other drugs or placebo plus other drugs. Other drugs consisted of a combination of ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone or available alternative. Bedaquiline was taken for 24 weeks and other drugs continued for 18-24 months. The primary efficacy endpoint was sputum culture conversion and time to conversion. Treatment failure was defined as lack of conversion or discontinuation of therapy. Culture conversion status was available in 67 subjects in the bedaquiline group and 66 in the placebo group. The rate of treatment success at week 24 was 77.6% in the treatment group and 57.6% in the placebo group (P = 0.014). At week 72, rates were 70.1% and 56.1% (P = 0.092). The time to sputum conversion was 83 days for bedaquiline and 125 days for placebo. This is an ongoing trial. In a 2-year, follow-up pilot study (n = 47) where bedaquiline was added to the first 8 weeks of therapy, it not only resulted in more rapid sputum conversion but may have also helped protect against acquired resistance to the other antitubercular drugs in the regimen.4 The most common adverse events were nausea (38%), arthralgia (33%), headache (28%), hemoptysis (18%), and elevation of liver aminotransferases of at least 3 × ULN.1
Multidrug-resistant tuberculosis are organisms resistant to isoniazid and rifampin.5 Infected patients typically need to be treated for at least 20 months. The introduction of bedaquiline for the first 24 weeks of therapy increases the rate of sputum conversion. However, long-term benefits and risks remain to be established.
1. Sirturo Prescribing Information. Titusville, NJ: Janssen Therapeutics; December 2012.
2. Haagsma AC, et al. Probing the interaction of the diarylquinoline TMC207 with its target mycobacterial ATP synthase. PLoS One 2011;6:e23575. Doi:10.1371/journal.pone.003575.
3. Koul A, et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J Biol Chem 2008;283:25273-25280.
4. Diacon AH, et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: Long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother 2012;56:3271-3276.
5. Centers for Disease Control and Prevention. Multidrug-Resistant Tuberculosis (MDR TB) Fact Sheet. http://www.cdc.gov/tb/publications/factsheets/drtb/mdrtb.htm. Accessed Feb. 23, 2013.