Bedaquiline is hepatically metabolized. The main enzyme involved is CYP3A4 which metabolizes bedaquiline into the N-monodesmethyl metabolite (M2). This metabolite is 4 to 6-times less active in terms of antimycobacterial potency.
贝达喹啉在肝脏中代谢。主要涉及的酶是CYP3A4，它将贝达喹啉代谢为N-单脱甲基代谢物（M2）。这个代谢物在抗分枝杆菌效力方面比原药低4到6倍。
Bedaquiline is hepatically metabolized. The main enzyme involved is CYP3A4 which metabolizes bedaquiline into the N-monodesmethyl metabolite (M2). This metabolite is 4 to 6-times less active in terms of antimycobacterial potency.
CYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2), which is 4 to 6-times less active in terms of antimycobacterial potency. Based on preclinical studies, bedaquiline is mainly eliminated in feces. The urinary excretion of unchanged bedaquiline was < 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant. After reaching Cmax, bedaquiline concentrations decline tri-exponentially. The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues.
After a single dose the mean AUC0-24 hr of the major metabolite M2 was 2 to 7-fold higher than AUC0-24 hr of bedaquiline in mice and was generally similar to 2-fold lower in rats and dogs.
Bedaquiline is a recently approved drug for the treatment of multidrug-resistant tuberculosis. Adverse cardiac and hepatic drug reactions to bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. Bedaquiline N-demethylation via CYP3A4 was confirmed as the major pathway in bedaquiline metabolism. In addition to CYP3A4, we found that both CYP2C8 and CYP2C19 contributed to bedaquiline N-demethylation. The Km values of CYP2C8, CYP2C19, and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3, and 8.5 uM, respectively. We also identified a novel metabolic pathway of bedaquiline that produced an aldehyde intermediate. In summary, this study extended our knowledge of bedaquiline metabolism, which can be applied to predict and prevent drug-drug interactions and adverse drug reactions associated with bedaquiline.
No chiral conversion of bedaquiline occurred in vivo after administration of bedaquiline to mice, rats, dogs, monkeys and humans. In hepatocytes and subcellular fractions from preclinical species and humans, the in vitro metabolism of (14)C-bedaquiline was via Phase I reactions and the most important pathway was N-demethylation to M2, which was followed by a second N-demethylation to M3, oxidation and epoxidation. M2 was the major circulating metabolite in all preclinical species as determined by radioactivity profiling and LC-MS/MS in the animals. No mass balance study with radiolabelled bedaquiline has been conducted in humans. It can therefore not be excluded that additional undetected metabolites may be formed in humans that are not formed in the animal species. M2-AUC0-24 hr plasma levels were generally comparable to 2-fold lower than those of bedaquiline in rats and dogs upon repeated administration of bedaquiline, and 3.5- to 4.5-fold lower in human subjects with MDR-TB. In addition to M2 and M3, a hydroxylated derivative of M2 (M20) and a dihydrodiol derivative of M2 (M11), were detected in human plasma. These two metabolites were also found in rats and dogs at similar relative concentrations.
IDENTIFICATION AND USE: Bedaquiline is a white solid. It is used as a antitubercular medication. HUMAN EXPOSURE AND TOXICITY: An increased risk of death was observed in patients receiving bedaquiline in a placebo-controlled clinical trial. In this study, there were 9 deaths in bedaquiline-treated patients; one death occurred during the 24 weeks of bedaquiline therapy and the median time to death for the other 8 patients was 329 days after the last dose of bedaquiline. Five of the 9 deaths in bedaquiline-treated patients and both deaths in placebo-treated patients were related to tuberculosis. The explanation for the imbalance in deaths in this study is not known; no correlation was demonstrated between death and sputum culture conversion, relapse, susceptibility to other antituberculosis drugs, HIV status, or disease severity. Bedaquiline and the M2 metabolite are cationic amphiphilic substances and induce phospholipidosis. The cells of the monocytic phagocytic system are affected in all species. Data from in vitro studies using human monocyte cell-line indicated that the phospholipidogenic potential was highest for the M2 metabolite followed by M3 and the parent compound. ANIMAL STUDIES: In mouse and rat, single oral doses of 800 mg/kg produced lethality preceded by signs of general toxicity. Mortalities in mouse and dog after single and repeated doses were principally attributed to skeletal muscle/myocardial degeneration and/or pancreatitis. Bedaquiline was not carcinogenic in rats up to the maximum tolerated dose of 10 mg/kg/day. In embryofetal toxicity studies conducted in rat and rabbit bedaquiline appeared to have no adverse effects on the embryonal development and the incidence of variations and malformations in fetuses in bedaquiline groups were within normal ranges. Exposure to bedaquiline and the M2 metabolite in rat at the high dose was considerable (up to 6-7 times higher compared with expected human exposure), while in rabbit a maximum exposure ratio of 2 were achieved. However, in rabbit the high dose of 100 mg/kg caused deaths, one abortion and increases in pre and postimplantation losses. Bedaquiline had no effect on fertility in females up to the highest dose tested, 24 mg/kg. Male fertility appeared to be decreased with a NOAEL of 5 mg/kg. No mutagenic or clastogenic effects were detected in the in vitro non-mammalian reverse mutation (Ames) test, in vitro mammalian (mouse lymphoma) forward mutation assay and an in vivo mouse bone marrow micronucleus assay.
Liver test abnormalities occur in 8% to 12% of patients treated with multiple drug regimens that include bedaquiline. These abnormalities are usually asymptomatic, mild-to-moderate in severity and self-limited in duration. In many instances, it is difficult to determine which of the antituberculosis medications accounts for the abnormalities, but monitoring of liver tests at monthly intervals is recommended during bedaquiline therapy. Clinically apparent liver injury has been reported with bedaquiline therapy, but the clinical features, course and outcome of these cases has not been described. At least three deaths from end stage liver disease have been described in patients taking bedaquiline, but the attribution of the hepatic failure to bedaquiline has been questioned. The management of multidrug resistant tuberculosis is challenging and should be under the direction of physicians with expertise in tuberculosis therapy.
◉ Summary of Use during Lactation:Data from two women taking bedaquiline and one of their breastfed infants indicate that exposure of the infant to the drug via breastmilk is substantial, with one infant having a therapeutic serum level. The clinical consequences of this exposure are unknown. The drug could protect the infant from multidrug-resistant tuberculosis, or could result in adverse effects. If bedaquiline is required by the mother, it is not a reason to discontinue breastfeeding. Monitor breastfed infants for adverse reactions, such as inadequate weight gain, liver toxicity, nausea, arthralgia, headache, hemoptysis, and chest pain.
◉ Effects in Breastfed Infants:A woman who was co-infected with HIV and rifampin-resistant tuberculosis took bedaquiline (dosage not stated) as part of her antituberculosis regimen, which consisted of pyrazinamide and other unnamed drugs. At the 1-month follow-up, the infant was small and not gaining weight well, but the mother was nauseated from her medication regimen and had also lost weight. Six months later after completion of the mother’s therapy, her infant’s weight was increasing, following the normal trajectory of the growth chart, and reaching her developmental milestones.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Pharmacologic interaction (increased risk of QT interval prolongation). Concomitant use with other drugs that prolong the QT interval (e.g., clofazimine, fluoroquinolones, macrolides) may result in additive or synergistic effects on the QT interval.
