Sirturo

Bedaquiline (Sirturo) instructions
Common name: Bedaquiline
Trade name: Sirturo
All names: Bedaquiline, Sirturo, Sirturo, Bedaquilin

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Indications
Sirturo is a diarylquinoline antimycobacterial agent indicated for use as part of combination therapy in adults (≥18 years of age) with multidrug-resistant tuberculosis (MDR-TB) when an effective treatment regimen is not otherwise available with Sirturo in reserve. Sirturo is not indicated for the treatment of latent, extrapulmonary or drug-sensitive tuberculosis.

Bedaquiline (Adult)
This product should be used under the guidance of an experienced physician. Recommended dosing for weeks 1-2: 400 mg orally once daily for 2 weeks, then weeks 3-24: 200 mg 3 times a week (with at least 48 hours between doses) for 22 weeks (total duration of treatment is 24 weeks).

Bedaquiline (Children)
<18 years: Safety and efficacy have not been established
Diarylquinoline Antimycobacteria As part of combination therapy in adults (≥18 years) with pulmonary multidrug-resistant tuberculosis (MDR-TB), CDC interim guidance recommends use of pediatric labeling on a case-by-case basis
Weeks 1-2: 400 mg PO Once a day for 2 weeks, then 200mg 3 times a week from Wednesday to 24th of the week for 22 weeks.
With a multidrug regimen that includes at least 4 other drugs, MDR-TB may persist for the entire 24 weeks.
Note: During the first 2 weeks of treatment: Do not make up missed doses, but continue with the usual dosing schedule. Beginning with Week 3: If a 200 mg dose is missed, the patient should take the missed dose as soon as possible and then resume the 3 times/week regimen.

Side effects and adverse reactions

(1) Adverse reactions reported (1-10%): increased transaminase (8.9%), increased blood amylase (2.5%)

(2) The most common adverse reactions (≥10%) reported were nausea (38%), arthralgia (32.9%), and headache (27.8%); additional adverse events reported in ≥10% and with a higher frequency than the placebo treatment group were hemoptysis and chest pain.

Warnings and Precautions
(1) QT prolongation may occur with Sirturo. Monitor ECG regularly.
(2) If significant ventricular arrhythmia occurs or QTcF interval > 500ms, discontinue taking Sirturo.
(3) The use of drugs that prolong the QT interval may cause additional QT prolongation. Monitor ECG more frequently.
(4) Liver-related adverse drug reactions have been reported using Sirturo. Monitor liver-related laboratory tests.
(5) Failure to comply with the treatment plan may lead to drug failure or drug resistance.
(6) Drug interactions: During treatment with this product, interactions with strong CYP3A4 inducers, such as rifamycins (rifampicin, rifapentine, and rifabutin) or moderate inducers, such as efavirenz, should be avoided.

Dosing in Special Populations
(1) No adjustment is required in patients with mild to moderate renal impairment or patients with mild to moderate hepatic impairment.
(2) Use with caution in patients with severe renal impairment.
(3) Use with caution and only when the benefits outweigh the risks in patients with severe hepatic impairment: Clinical monitoring for Sirturo-related adverse reactions is recommended.
(4) Medication for children: It is not clear yet.
(5) Medication for elderly patients: Due to limited data, differences in results and specific risks for patients aged 65 and above cannot be ruled out.
(6) Medication for pregnant and lactating women: Medication for lactating women: Since breastfed babies may have adverse reactions, the benefits of breastfeeding to the baby and the benefits of drug treatment to the mother must be weighed to decide whether to stop breastfeeding or give up treatment with this product.

Mechanism of action

The unique and specific anti-tuberculosis (TB) site of bedaquiline is the proton pump of Mycobacterium tuberculosis ATP synthase. ATP synthase is the key enzyme for Mycobacterium tuberculosis to synthesize ATP. When the oligomers of ATP synthase and lipoprotein subunit c bind to bedaquiline, they can inhibit the synthesis of ATP, leading to the death of bacteria. Bedaquiline has a new anti-TB mechanism and has no cross-resistance with existing anti-TB drugs. The gene sequence of subunit c of ATP synthase was named atpE. Its amino acid sequence is highly conserved. The mechanism of resistance of Mycobacterium tuberculosis to bedaquiline is that the mutation of amino acid 63 or 66 of atpE reduces the binding ability of bedaquiline to the c subunit of ATP synthase.

Contraindications
1. People who are allergic to this product;
2. Relative contraindications for people with severe heart, liver, kidney and other dysfunctions.

Save
Bedaquiline is packaged in 188 tablets/bottle/box. Storage needs to be in a dark place, sealed, and stored below 30°C. Validity period is 24 months.

Treatment Effect
Bedaquiline is the first new anti-tuberculosis drug to be launched in recent years. As the first drug approved by the U.S. Food and Drug Administration to treat multidrug-resistant tuberculosis, it will play a huge role in the field of tuberculosis prevention and treatment.

A multinational phase 2b randomized, double-blind controlled trial. The researchers included adults with recently diagnosed multidrug-resistant tuberculosis (MDR-TB) who were sensitive to at least three of five drugs. Seventy-nine patients were randomized to receive bedaquiline 400 mg once a day for 2 weeks, followed by 200 mg three times a week for 22 weeks. 81 patients were randomized to receive placebo treatment. Investigators followed for 120 weeks and analyzed sputum samples at baseline, weeks 8, 24, and 72.

The sputum negative conversion rate of patients in the bedaquiline group was significantly faster than that in the placebo group (125 days vs 83 days; bedaquiline hazard ratio, 2.44; 95% confidence interval, 1.57-3.80; P<0.01). The sputum negative conversion rate was significantly higher in the bedaquiline group at week 24 (79% vs 58%; P = 0.008) and week 120 (62% vs 44%; P = 0.04). At week 120, the clinical cure rates in the bedaquiline and placebo groups were 58% and 32% respectively (P=0.003). Patients in the bedaquiline group had a lower risk of developing other forms of drug-resistant tuberculosis than those in the placebo group (2 patients vs. 16 patients).