Bedaquiline

Bedaquiline is an Antitubercular agent belonging to Broad-spectrum antibiotic/ Drug Resistant TB.

Bedaquiline is used in the Treatment of multidrug-resistant, pulmonary tuberculosis (MDR-TB)

Bedaquiline is Well absorbed and Increased bioavailability with food.

The Volume of distribution is Approx 164 L with Plasma protein binding: >99.9% and get Metabolised in the liver by CYP3A4 isoenzyme to form less potent N-monodesmethyl metabolite (M2). It get excreted Mainly via faeces; urine (≤0.001% as unchanged drug). Terminal elimination half-life: Approx 5.5 months (range: 2-8 months).

The Tmax of Bedaquiline was within 5 hours. The Cmax of Bedaquiline was 5.5 μg/ml.

Bedaquiline shows common side effects like Chest pain , coughing or spitting up blood , dark-colored urine, decreased appetite , fever , general feeling of tiredness

Bedaquiline is available in the form of Tablets .

Bedaquiline is available in India, Germany, Canada, Italy.

Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits the proton pump of mycobacterial ATP (adenosine 5’-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis. Bacterial death occurs as a result of bedaquiline.

Bedaquiline is used in the Treatment of multidrug-resistant, pulmonary tuberculosis (MDR-TB).

Bedaquiline is approved for use in the following clinical indications

● Tuberculosis, multidrug resistant, pulmonary: Treatment of multidrug-resistant, pulmonary tuberculosis (MDR-TB) as part of combination therapy in pediatric patients ≥5 years of age (weighing ≥15 kg) and adults when an effective treatment regimen cannot otherwise be provided.

● Limitations of use: Not for use in extrapulmonary TB, latent TB infection, drug-sensitive TB, or treatment of other mycobacteria. Clinical data in patients with HIV-1 and MDR-TB coinfection are limited.

Bedaquiline is available in various strengths as 20 mg, 100 mg.

Bedaquiline is available in the form of Tablets

• Dosage Adjustment in Kidney Patient

Mild-to-moderate renal impairment: No dosage adjustment necessary.

Severe renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor for adverse reactions.

End-stage renal disease (ESRD) on intermittent hemodialysis (IHD) or peritoneal dialysis (PD): There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor for adverse reactions. Bedaquiline is highly protein bound and not likely to be removed by dialysis.

• Dosage Adjustment in Hepatic impairment Patient

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution and monitor for adverse reactions.

● Dosage Adjustment for Pediatric Patients

Active tuberculosis (multidrug-resistant), pulmonary: Note: Always administer as part of a multidrug therapy regimen of ≥3 to 4 additional drugs active against the patient's M. tuberculosis isolate.

Children ≥5 years and Adolescents:

15 to <30 kg:

Weeks 1 and 2: Oral: 200 mg once daily.

Weeks 3 to 24: Oral: 100 mg 3 times weekly with at least 48 hours between doses; total weekly dose: 300 mg/week.

≥30 kg:

Weeks 1 and 2: Oral: 400 mg once daily.

Weeks 3 to 24: Oral: 200 mg 3 times weekly with at least 48 hours between doses; total weekly dose: 600 mg/week.

Concerns related to adverse effects:

• Hepatic effects: Increased risk of hepatic reactions; avoid alcohol intake and other known hepatotoxic drugs, especially in patients with impaired hepatic function. Monitor AST, ALT, alkaline phosphatase, bilirubin, and symptoms of liver dysfunction (eg, fatigue, nausea, anorexia, jaundice, dark urine, liver tenderness, and hepatomegaly) at baseline and monthly during therapy, and as needed. Monitor more frequently if patient has underlying hepatic disease or is receiving concomitant drugs . Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening hepatic disease occurs. Discontinue use if aminotransferase elevations are accompanied by total bilirubin elevation >2 times ULN, aminotransferase elevations are >8 times ULN, or aminotransferase elevations are >5 times ULN and continue for >2 weeks.

Bedaquiline may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

It is not known if Bedaquiline is present in breast milk.

Bedaquiline is not significantly absorbed when administered orally, limiting any potential exposure via breast milk. The manufacturer recommends that caution be exercised when administering Bedaquiline to breastfeeding women. Patients with multidrug-resistant tuberculosis and a sputum smear-positive test should avoid breastfeeding when possible.

Concentrations in the mother’s milk approach those found in the serum. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pregnancy Category B.

Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to bedaquiline. In these studies, the corresponding plasma exposure (AUC) was 2-fold higher in rats compared to humans. There are, however, no adequate and well-controlled studies of Bedaquiline in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Administration with food increases bioavailability. Avoid concomitant use with alcohol as it may increase the risk of hepatotoxicity. May reduce exposure and therapeutic effect with St. John’s wort; avoid concomitant use.

• Common Adverse effects

Drowsiness, somnolence, dizziness, headache, lethargy, depression, tremor, dysarthria, hyperreflexia, paraesthesia, nervousness, anxiety, vertigo, confusion, disorientation, loss of memory, paresis, major and minor clonic seizures

• Less Common Adverse effects:

Psychosis (possibly w/ suicidal tendencies), personality changes, hyperirritability, aggression; elevated serum aminotransferase levels, esp in patients w/ pre-existing liver disease.

• Rare Adverse effects

Hypersensitivity reactions including rash and photosensitivity; cardiac arrhythmias and sudden CHF.

May reduce exposure and therapeutic effect with moderate or strong CYP3A4 inducers (e.g. rifampicin, efavirenz, carbamazepine, phenytoin); avoid concomitant use. May increase serum concentration with moderate or strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, ciprofloxacin, erythromycin); avoid concomitant use for >14 consecutive days unless necessary. Concomitant use with QT interval prolonging drugs including ketoconazole, fluoroquinolones (e.g. moxifloxacin, gatifloxacin), macrolide antibiotics (e.g. clarithromycin), and clofazimine may cause additive or synergistic effects on the QT interval. Hepatotoxic drugs may increase the risk of hepatic-related adverse reactions; avoid concomitant use.

The common side effects of Bedaquiline include the following swelling, rapid weight gain, little or no urination, Severe dizziness, Spinning sensation, and Ringing or Roaring.

There is no experience with the treatment of acute overdose with bedaquiline. General measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) should be taken in case of deliberate or accidental overdose. Removal of unabsorbed bedaquiline may be achieved by gastric lavage or aided by the administration of activated charcoal. Since bedaquiline is highly protein-bound, dialysis is not likely to significantly remove bedaquiline from plasma.

Pharmacodynamic

Bedaquiline is primarily subjected to oxidative metabolism leading to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4 to 6-fold lower) compared to the parent compound. M2 concentrations appeared to correlate with QT prolongation. Bedaquiline inhibits mycobacterial TB at a minimal inhibitory concentration (MIC) from 0.002-0.06 μg/ml and with a MIC50 of 0.03 μg/ml. Furthermore, bacteria that have smaller ATP stores (usually in dormant, nonreplicating bacilli) are more susceptible to bedaquiline.

Pharmacokinetics

• Absorption: Well absorbed. Increased bioavailability with food. Time to peak plasma concentration: Approx 5 hours.
• Distribution: Volume of distribution: Approx 164 L. Plasma protein binding: >99.9%.
• Metabolism: Metabolised in the liver by CYP3A4 isoenzyme to form less potent N-monodesmethyl metabolite (M2).
• Excretion: Mainly via faeces; urine (≤0.001% as unchanged drug). Terminal elimination half-life: Approx 5.5 months (range: 2-8 months).

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Bedaquiline -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Bedaquiline
• https://europepmc.org/article/med/6988203