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.

Bedaquiline has activity against M. tuberculosis complex strains with a minimal inhibitory concentration (MIC) in the range of ≤0.008 to 0.25 mg/L. The N-monodesmethyl 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, Mycobacterium flavescens and non-mycobacterial species are considered inherently resistant to bedaquiline.

The pharmacokinetic properties of bedaquiline have been evaluated in healthy adults and in patients 2 years of age and older with active TB. Exposure to bedaquiline was lower in patients with pulmonary TB due to M. tuberculosis resistant to at least rifampicin and isoniazid than in healthy adults.

In adult patients with pulmonary TB, following 2 weeks of 400 mg bedaquiline once daily, mean (SD) C_max and AUC_24h, ng∙h/mL were 3060 (1124) ng/mL and 41510 (15064) ng∙h/mL, respectively, for bedaquiline and 326 (135) ng/mL and 7267 (3029) ng∙h/mL, respectively, for the M2 metabolite. Following 38 weeks of 200 mg bedaquiline three times weekly, mean (SD) C_max and AUC_168h, ng∙h/mL were 1787 (666) ng/mL and 168376 (74476) ng∙h/mL, respectively, for bedaquiline and 246 (103) ng/mL and 39540 (17220) ng∙h/mL, respectively, for the M2 metabolite.

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 700 mg single-dose and once daily 400 mg for 14 days. 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 humans. The plasma protein binding of its active metabolite, M2, in humans is at least 99.8%. In animals, bedaquiline and M2 are extensively distributed to most tissues, however, brain uptake is low.

Biotransformation

CYP3A4 is the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation and metabolism of 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 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 participants with moderate hepatic impairment (Child-Pugh B) demonstrated exposure to bedaquiline and M2 (AUC_672h) was 19% lower compared to healthy participants. 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 2 years to less than 18 years, the expected average (90% prediction interval) plasma exposure of bedaquiline (AUC_168h) at Week 24 when treated with the recommended dosing regimen based on weight is:

• For 7 kg to less than 15 kg: 123 μg∙h/mL (49.4 to 307 μg∙h/mL)
• For 15 kg to less than 30 kg: 152 μg∙h/mL (54.3 to 313 μg∙h/mL)
• For 30 to 40 kg: 229 μg∙h/mL (68.0 to 484 μg∙h/mL)
• For greater than 40 kg: 165 μg∙h/mL (51.2 to 350 μg∙h/mL)

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 to 249 μg∙h/mL).

The pharmacokinetics of bedaquiline in paediatric patients less than 2 years of age or weighing less than 7 kg have not been established.

Elderly patients

In a population pharmacokinetic analysis of tuberculosis patients treated with bedaquiline, age was not found to influence the pharmacokinetics of bedaquiline.

In five patients 65 to 69 years of age, the systemic bedaquiline exposure was similar to that of other adults.

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 lower bedaquiline exposure in Black patients was not associated with lower efficacy in clinical trials, and no dose adjustment is needed.

Gender

In a population pharmacokinetic analysis of tuberculosis patients treated with bedaquiline, no clinically relevant differences 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 patients with pulmonary 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 epididymides 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 than 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 45 mg/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 mineralisation (partial recovery in males, and no recovery in females within 8 weeks after end of exposure). The NOAEL corresponds to a plasma AUC_24h of 13.1 and 35.6 μg∙h/mL for bedaquiline (~0.7x clinical dose) and 10.5 and 16.3 μg∙h/mL for the N-monodesmethyl 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.