Janssen's Sirturo

Sirturo (bedaquiline) was approved by the FDA on December 31, 2012, as a part of combination therapy against pulmonary multidrug-resistant tuberculosis (MDR-TB) in patients ≥18 years of age.¹ Sirturo should be reserved as a last-line alternative for patients with MDR-TB. Patients with latent, extra-pulmonary, or drug-sensitive tuberculosis or patients with infections caused by non-tuberculous mycobacteria should not receive Sirturo. In addition, Sirturo carries a black box warning for an increased risk of death based on the results of a trial in which 9 of 79, or 11.4%, of patients taking Sirturo died versus 2 of 81, or 2.5%, of patients taking placebo. Sirturo also carries a black box warning for QT interval prolongation.²

PHARMACOLOGY AND PHARMACOKINETICS

Sirturo inhibits mycobacterial ATP (adenosine 5’-triphosphate) synthase, an enzyme in the Mycobacterium tuberculosis bacterium that aids in energy production. Bacteria may develop resistance to Sirturo through mutations of the atpE gene.²

Sirturo oxidizes in the human body, forming a metabolite known as M2 with 4- to 6-times lower activity than the parent compound. After single-dose oral administration of Sirturo, plasma concentrations peak within approximately 5 hours. The elimination half-life of Sirturo and its metabolite is roughly 5.5 months.²

Results of preclinical studies indicate that excretion is primarily fecal. Because renal and hepatic elimination of Sirturo is minimal, the manufacturer does not recommend dose adjustment in patients with mild to moderate hepatic impairment, although Sirturo has not been studied in patients with severe hepatic impairment. Despite the very small percentage of Sirturo eliminated in urine, the manufacturer recommends caution in patients with severe renal impairment or end-stage renal disease, and patients undergoing dialysis.²

DOSAGE AND ADMINISTRATION

Each 100-mg tablet of Sirturo should be swallowed whole with a full glass of water. To maximize bioavailability, Sirturo should be taken with food. Compared with fasting-state administration, administration with food approximately doubles the bioavailability of Sirturo.²

Patients starting treatment should take 400 mg once daily with food for the first 2 weeks and 200 mg 3 times per week with food for the next 22 weeks for a total duration of therapy of 24 weeks. If a dose is missed during the first 2 weeks of therapy, patients should not take a double dose to compensate for the missed dose. Missed doses should be taken as soon as remembered with the 3 times weekly regimen, although patients taking Sirturo 3 times weekly must separate each subsequent dose by at least 48 hours.²

Any patient taking Sirturo should be taking at least 3 other drugs active against the individual patient’s strain of MDRTB, as determined by a susceptibility test.²

CLINICAL TRIALS

In clinical trials with Sirturo, investigators randomized 160 patients with MDRTB to receive several drugs including ethionamide, kanamycin, pyrazinamide, ofloxacin, and/or cycloserine/terizidone with Sirturo or placebo. Of patients in this trial, the majority (63%) were male, and 15% had HIV infection. The median age of study participants was 34 years. Seventy-nine patients received Sirturo, and the remaining 81 received placebo with background therapy.²

After 24 weeks of treatment, patients continued to receive other medications until 1 year after each patient’s first report of an MDR-TB—free sputum culture, which defined treatment success.

After 24 weeks, 77.6% of patients receiving Sirturo attained treatment success versus 57.6% of patients receiving placebo (P = .014). Discontinuation rates after 24 weeks were 14.9% with active treatment and 18.2% with placebo. The advantage of Sirturo had ceased to be statistically significant by week 72, at which point 70.1% of patients receiving Sirturo attained treatment success, and 56.1% of patients receiving placebo attained treatment success (P = .092). About one-fourth (25.4%) of patients receiving active treatment discontinued therapy after 72 weeks, compared with 33.3% of patients receiving placebo.²

WARNINGS AND PRECAUTIONS

Use of Sirturo with strong CYP3A4 inhibitors may lead to increased exposure. In healthy volunteers, ketoconazole increased exposure in a mean of 22%, 9%, and 33% in 3 separate evaluations. Through CYP3A4 induction, rifampin reduced exposure to Sirturo by 52%. The manufacturer recommends avoidance of CYP3A4 inhibitors, including rifamycin-type antituberculin drugs, for more than 14 consecutive days. Under some circumstances, this recommendation may be circumvented if the potential benefits of therapy outweigh the risks of treatment.²

In clinical trials, investigators observed no major pharmacokinetic interactions with ethambutol, kanamycin, pyrazinamide, ofloxacin, or cycloserine. Twice daily dosing of 400 mg lopinavir/100 mg ritonavir for 24 days in healthy volunteers increased exposure to Sirturo by 22%. Four weeks of nevirapine 200 mg twice daily did not induce clinically relevant changes in levels of Sirturo.²

In a 120-week follow-up, a greater proportion of patients treated with Sirturo died than patients treated with placebo (11.4% versus 2.5%). The cause of this increase in mortality remains unexplained. The manufacturer recommends electrocardiographic monitoring at weeks 2, 12, and 24, after starting treatment. Patients with abnormal QT prolongation should receive regular testing for electrolyte levels. Patients receiving Sirturo should undergo regular liver enzyme monitoring and should avoid using of hepatotoxic drugs, including alcohol.²

Common adverse events in clinical trials included nausea, arthralgia, and headache, each of which occurred in more than 10% of patients. Hemoptysis and chest pain also occurred in more than 10% of patients receiving Sirturo, and occurred with a higher frequency than in patients receiving placebo. For a complete discussion of potential adverse events and drug interactions, please consult the product package insert.² SPT

References:

1. FDA News Release: Sirturo. Food and Drug Administration website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm. Accessed November 2013.

2. Sirturo (bedaquiline) tablets [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP; 2012.

About the Author

Michael R. Page, PharmD, RPh, earned his PharmD from the Ernest Mario School of Pharmacy at Rutgers University. He has worked as a community pharmacist at CVS Pharmacy and is currently clinical editor in clinical and scientific affairs at Pharmacy Times.