Bedaquiline

Bedaquiline
Fast-track approval for treatment of tuberculosis
May 3, 2013

Bedaquiline (Sirturo) represents a new class of anti-TB drugs called diarylquinolines that have a novel mechanism of action to stop replication of TB. It has FDA approval for treatment of multi-drug resistant pulmonary TB. The drug has not been evaluated with extra-pulmonary TB affecting the CNS. Standard treatment involves a four-drug regimen with isoniazid, rifampin and pyrazinamide (PZA). A recent meta-analysis showed the percentage of patients dying from TB was 3% in non-HIV patients, 9.2% in HIV-infected patients and 30.9% in HIV-infected patients with multi-drug resistant TB. This drug achieved fast-track approval by the FDA due to risks associated with multi-drug resistant TB.
Recent clinical trials included patients with pulmonary TB and used the same dosing strategy (400 mg orally twice daily for two weeks followed by 200 mg three times per week). The clinical endpoint was the time to convert to a normal sputum culture (culture conversion), which indicates cessation of mycobacterium growth.
A phase 2 study assessed the mycobacterial activity and safety of using bedaquiline added to standard therapy. Adult patients with the presence of acid-fast bacilli in sputum that were resistant to isoniazid and rifampin were included. Patients with uncontrolled HIV were excluded.
This eight-week study was conducted in South Africa and was a double-blind, placebo-controlled study. The study group (n = 47) had a median age of 33 years, 74% were male and 87% were HIV-negative. The study drug significantly decreased the time to culture conversion (p = 0.003), and resulted in a greater proportion of patients who were culture negative (48% versus 9%). Strengths of the study were achieving a 97% medication adherence rate.
A two-year follow-up of these patients found 23 patients (48.9%) in both treatment arms had discontinued the study. At week 24, 81% in the bedaquiline group and 65.2% in the placebo group maintained culture conversion.
Bedaquiline is effective against mycobacterium isolates resistant to isoniazid, rifampin PZA and others.5 It acts by inhibiting a proton pump affecting the cellular enzyme, ATP synthase, which depletes the cell’s stores of ATP and ultimately decreases mycobacterium survival.5,6 It has bactericidal activity and a minimum inhibitory concentration that is similar or lower than current drugs.
Dosage, Costs, Pharmacokinetics
Bedaquiline is used in combination with at least three other drugs. The initial dose is 400 mg orally once daily for two weeks, followed by a maintenance dose of 200 mg orally three times per week for 22 weeks. The treatment continues for a total of 24 weeks. Maintenance doses should be scheduled on specific days (e.g., Monday-Wednesday-Friday) to promote adherence.
In patients who are non-adherent or fail therapy, use Directly Observed Therapy. The doses are available in 100 mg tablets, and should be taken with water and food. Patients should store their medications in the original container. Tablets stored in a medication organizer can break down due to exposure to light and moisture.
Bedaquiline has a long half-life for the active drug (164 days) and M2 metabolite (159 days).1,4,6 The metabolite is less active than the parent drug. The drug is slowly released from the peripheral tissues, which accounts for the persistent concentration in the blood. The maximum concentration is achieved six hours after taking a 400 mg dose.
The drug is highly protein-bound (99%). It is metabolized by the hepatic cytochrome P450 3A4 enzyme and is susceptible to drug interactions by this pathway. The drug should be used cautiously in patients with severe kidney dysfunction. The benefits should outweigh the risks if used with severe liver dysfunction.
Drug Interactions & Side Effects
Common side effects are headache and nausea. Patients also reported arthralgia, hemoptysis and rash. The FDA prescribing information warns about the potential for developing harmful ventricular arrhythmias (long QT syndrome). In follow-up studies, QT interval was prolonged but there were no readings higher than 500 msec.
The proportion of patients dying during one clinical study was greater in the bedaquiline group versus the placebo group. The reasons for this are unclear. Therefore, the boxed warning cautions to only select this drug for patients who are not candidates for other approved drugs. This underscores the need to closely monitor patients with frequent follow-ups. Some adverse effects identified in clinical studies were not found to be significantly different than the placebo-group and include non-cardiac chest pain and deafness.
Take a medication history and advise patients to stop any CYP3A4 inhibitors for 14 days before starting bedaquiline.1 Carefully select and monitor drug therapy to avoid interactions that may cause QT interval prolongation on the electrocardiogram.
Drugs that may have an additive effect on prolonging the QT interval include clofazimine (a drug for TB), tricyclic antidepressants, dofetilide and others. Drugs that inhibit CYP3A4 are macrolide (erythromycin, clarithromycin) and fluoroquinolone (levofloxacin) antibiotics, and ketaconazole (antifungal). Rifampin, a main-stay of therapy for TB, and others in the class (rifabutin, rifapentine) are hepatic enzyme inducers and may decrease levels of bedaquiline. If used in HIV co-infected patients, current literature should be evaluated to determine if new information is available on interactions with HIV drugs.
Frequent monitoring should include checking hepatic transaminases (AST, ALT, alkaline phosphatase), total bilirubin and uric acid (hyperuricemia). Check an electrocardiogram to measure QT intervals at baseline, weeks two, 12 and 24. Order and maintain electrolytes within normal limits (calcium, magnesium, potassium)