Bedaquiline

Bedaquiline is a diarylquinoline. Bedaquiline specifically inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, an essential enzyme for the generation of energy in Mycobacterium tuberculosis. The inhibition of ATP synthase leads to bactericidal effects for both replicating and non-replicating tubercle bacilli.

Pharmacodynamic effects

Bedaquiline has activity against Mycobacterium tuberculosis with a minimal inhibitory concentration (MIC) for drug-sensitive as well as drug-resistant strains (multi-drug resistant including preextensively drug resistant strains, extensively drug resistant strains) in the range of ≤0.008-0.12 mg/l. The Nmonodesmethyl metabolite (M2) is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (3 to 6-fold lower) compared to the parent compound.

The intracellular bactericidal activity of bedaquiline in primary peritoneal macrophages and in a macrophage-like cell line was greater than its extracellular activity. Bedaquiline is also bactericidal against dormant (non-replicating) tubercle bacilli. In the mouse model for TB infection, bedaquiline has demonstrated bactericidal and sterilizing activities.

Bedaquiline is bacteriostatic for many non-tuberculous mycobacterial species. Mycobacterium xenopi, Mycobacterium novocastrense, Mycobacterium shimoidei and non-mycobacterial species are considered inherently resistant to bedaquiline.

The pharmacokinetic properties of bedaquiline have been evaluated in adult healthy subjects and in multi-drug resistant tuberculosis-infected patients 5 years of age and older. Exposure to bedaquiline was lower in multi-drug resistant tuberculosis-infected patients than in healthy subjects.

Absorption

Maximum plasma concentrations (C_max) are typically achieved at about 5 hours post-dose. C_max and the area under the plasma concentration-time curve (AUC) increased proportionally up to the highest doses studied (700 mg single-dose and once daily 400 mg multiple doses). Administration of bedaquiline with food increased the relative bioavailability by about 2-fold compared to administration under fasted conditions. Therefore, bedaquiline should be taken with food to enhance its oral bioavailability.

Distribution

The plasma protein binding of bedaquiline is >99.9% in all species tested, including human. The plasma protein binding of the N-monodesmethyl metabolite (M2) in humans is at least 99.8%. In animals, bedaquiline and its active N-monodesmethyl metabolite (M2) are extensively distributed to most tissues, however, brain uptake was low.

Biotransformation

CYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2).

In vitro, bedaquiline does not significantly inhibit the activity of any of the CYP450 enzymes tested (CYP1A2, CYP2A6, CYP2C8/9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A4/5 and CYP4A) and does not induce CYP1A2, CYP2C9 or CYP2C19 activities.

Bedaquiline and M2 were not substrates of P-gp in vitro. Bedaquiline was a weak OCT1, OATP1B1 and OATP1B3 substrate in vitro, while M2 was not. Bedaquiline was not a substrate of MRP2 and BCRP in vitro. Bedaquiline and M2 did not inhibit the transporters P-gp, OATP1B1, OATP1B3, BCRP, OAT1, OAT3, OCT1, OCT2, MATE1 and MATE2 at clinically relevant concentrations in vitro. An in vitro study indicated a potential for bedaquiline to inhibit BCRP at the concentrations achieved in the intestine after oral administration. The clinical relevance is unknown.

Elimination

Based on the preclinical studies, the bulk of the administered dose is eliminated in faeces. The urinary excretion of unchanged bedaquiline was <0.001% of the dose in clinical studies, indicating that renal clearance of unchanged active substance is insignificant. After reaching C_max, bedaquiline concentrations decline tri-exponentially. The mean terminal elimination half-life of both bedaquiline and the active N-monodesmethyl metabolite (M2) is about 5 months (ranging from 2 to 8 months). This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues.

Special populations

Hepatic impairment

A single-dose study of bedaquiline in 8 subjects with moderate hepatic impairment (Child-Pugh B) demonstrated exposure to bedaquiline and M2 (AUC_672h) was 19% lower compared to healthy subjects. No dose adjustment is deemed necessary in patients with mild or moderate hepatic impairment. Bedaquiline has not been studied in patients with severe hepatic impairment.

Renal impairment

Bedaquiline has mainly been studied in patients with normal renal function. Renal excretion of unchanged bedaquiline is insignificant (<0.001%).

In a population pharmacokinetic analysis of tuberculosis patients treated with bedaquiline 200 mg three times a week, creatinine clearance (range: 40 to 227 ml/min) was not found to influence the pharmacokinetic parameters of bedaquiline. It is therefore not expected that mild or moderate renal impairment will have a clinically relevant effect on the exposure to bedaquiline. However, in patients with severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease requiring haemodialysis or peritoneal dialysis, bedaquiline concentrations may be increased due to alteration of active substance absorption, distribution, and metabolism secondary to renal dysfunction. As bedaquiline is highly bound to plasma proteins, it is unlikely that it will be significantly removed from plasma by haemodialysis or peritoneal dialysis.

Paediatric patients

In paediatric patients aged 5 years to less than 18 years and weighing 15 kg to less than 30 kg, the average plasma exposure of bedaquiline (AUC_168h) at week 24 is predicted to be 152 mcg*h/mL (90% prediction interval: 54.3-313 mcg*h/mL) when treated with the recommended weight based dosing regimen. In paediatric patients weighing from 30 to 40 kg, the average plasma exposure of bedaquiline (AUC_168h) at week 24 is predicted to be higher (average: 229 µg*h/mL; 90% prediction interval: 68.0-484 mcg*h/mL) compared to adult patients. In paediatric patients aged 5 years to less than 18 years and weighing greater than 40 kg, the average plasma exposure of bedaquiline (AUC_168h) at week 24 is predicted to be 165 mcg*h/mL (90% prediction interval: 51.2-350 mcg*h/mL) when treated with the recommended weight based dosing regimen. The average plasma exposure of bedaquiline (AUC_168h) at week 24 in adults was predicted to be 127 µg*h/mL (90% prediction interval: 39.7-249 mcg*h/mL).

The pharmacokinetics of bedaquiline in paediatric patients less than 5 years of age or weighing less than 15 kg have not been established.

Elderly patients

There is limited clinical data (n=2) on the use of bedaquiline in tuberculosis patients aged 65 years and older.

In a population pharmacokinetic analysis of tuberculosis patients (age range 18 years to 68 years) treated with bedaquiline age was not found to influence the pharmacokinetics of bedaquiline.

Race

In a population pharmacokinetic analysis of tuberculosis patients treated with bedaquiline, exposure to bedaquiline was found to be lower in Black patients than in patients from other race categories. This low exposure was not considered to be clinically relevant as no clear relationship between exposure to bedaquiline and response has been observed in clinical trials. Furthermore, response rates in patients that completed the bedaquiline treatment period were comparable between different race categories in the clinical trials.

Gender

In a population pharmacokinetic analysis of tuberculosis patients treated with bedaquiline no clinically relevant difference in exposure between men and women were observed.

Animal toxicology studies have been conducted with bedaquiline administration up to 3 months in mice, up to 6 months in rats, and up to 9 months in dogs. The plasma bedaquiline exposure (AUC) in rats and dogs was similar to that observed in humans. Bedaquiline was associated with effects in target organs which included monocytic phagocytic system (MPS), skeletal muscle, liver, stomach, pancreas and heart muscle. All of these toxicities except effects on MPS were monitored clinically. In the MPS of all species, pigment-laden and/or foamy macrophages were also seen in various tissues, consistent with phospholipidosis. The significance of phospholipidosis in humans is unknown. Most of the observed changes occurred after prolonged daily dosing and subsequent increases in plasma and tissue concentrations of the active substance. After treatment cessation, all indications of toxicity exhibited at least partial recovery to good recovery.

In a rat carcinogenicity study, bedaquiline, at the high doses of 20 mg/kg/day in males and 10 mg/kg/day in females, did not induce any treatment-related increases in tumour incidences. Compared to the exposures (AUC) observed in subjects with MDR-TB in the bedaquiline Phase II trials, the exposures (AUC) in rats at high doses were similar in males and 2-fold higher in females for bedaquiline, and 3-fold higher in males and 2-fold higher in females for M2.

In vitro and in vivo genotoxicity tests indicated that bedaquiline did not have any mutagenic or clastogenic effects.

Bedaquiline had no effects on fertility when evaluated in female rats. Three of 24 male rats treated with high bedaquiline doses failed to produce offspring in the fertility study. Normal spermatogenesis and a normal amount of spermatozoa in the epidydimides were noted in these animals. No structural abnormalities in the testes and epididymides were seen after up to 6-months of bedaquiline treatment. No relevant bedaquiline-related effects on developmental toxicity parameters were observed in rats and rabbits. The corresponding plasma exposure (AUC) was 2-fold higher in rats compared to humans. In the rat, no adverse effects were observed in a pre- and post-natal development study at maternal plasma exposure (AUC) similar to humans and exposure in the offspring 3-fold higher than in adult humans. There was no effect of maternal treatment with bedaquiline at any dose level on sexual maturation, behavioural development, mating performance, fertility or reproductive capacity of the F1 generation animals. Body weight decreases in pups were noted in high dose groups during the lactation period after exposure to bedaquiline via milk and were not a consequence of in utero exposure. Concentrations of bedaquiline in milk were 6- to12-fold higher that the maximum concentration observed in maternal plasma.

In a juvenile rat toxicity study, the no observed adverse effect level (NOAEL) was 15 mg/kg/day (maximum dose 45mg/kg/day) for observations of diffuse inflammation and/or degeneration in skeletal muscle (reversible), oesophagus (reversible) and tongue (reversible), liver hypertrophy (reversible) and corticomedullary renal mineralization (partial recovery in males, and no recovery in females within 8 weeks after end of exposure). The NOAEL corresponds to a plasma AUC24h of 13.1 and 35.6 mcg.h/mL for bedaquiline (~0.7x clinical dose) and 10.5 and 16.3 mcg.h/mL for the Nmonodesmethyl metabolite of bedaquiline (M2) in males and females (~1.8x clinical dose), respectively.

Environmental risk assessment (ERA)

Environmental risk assessment studies have shown that bedaquiline has the potential to be persistent, bioaccumulative and toxic to the environment.