Bedaquiline Metabolism: Enzymes and Novel Metabolites

Abstract

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 K m values of CYP2C8, CYP2C19, and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3, and 8.5 mM, 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. IntroductionMultidrug-resistant tuberculosis (MDR-TB) is defined as tuberculosis (TB) with resistance to at least isoniazid and rifampicin, the two most powerful first-line anti-TB drugs (Chang and Yew, 2013). There were approximately 0.31 million incident cases of MDR-TB among patients with TB in 2011. Treatment of MDR-TB requires second-line anti-TB agents given over a period of 18-24 months (Mukherjee et al., 2004). Significant side effects and a high patient death rate were observed during long-term treatment against MDR-TB (World Health Organization, 2013). Thus, there is an urgent need to develop a shorter and less toxic regimen to reduce the side effects and mortality associated with MDR-TB chemotherapy.Bedaquiline (BDQ) was recently approved by the U.S. Food and Drug Administration (FDA, 2012b) for the treatment of MDR-TB . BDQ is a diarylquinoline with a novel mechanism of action specifically inhibiting mycobacterial ATP synthase (Cole and Alzari, 2005). In a randomized phase II placebo-controlled clinical trial among patients with MDR-TB, 48% of patients who received BDQ in combination with a standard MDR regimen showed a conversion to negative culture in 8 weeks compared with 9% in the placebo group that received the standard MDR regimen (Diacon et al., 2009). After 24 weeks, the proportion of patients that reached treatment success was 78.8% in the BDQ group and 57.6% in the placebo group (Diacon et al., 2012). However, BDQ carries a boxed warning indicating that this drug can cause QT prolongation, which could lead to an abnormal and potentially fatal heart rhythm (FDA, 2012a). In addition, the rate of drug-related hepatic disorders in the BDQ group (8.8%) was higher than that in the placebo group (1.9%) (FDA, 2012a).Illustration of BDQ metabolism will provide valuable information to predict and prevent drug-drug interactions and adverse drug reactions associated with BDQ. CYP3A4 is involved in BDQ metabolism, leading to the formation of a dominant but less active N-desmethyl metabolite (Janssen Pharmaceutical Companies, 2012). BDQ and its metabolites, including N-desmethyl BDQ, N-didesmeth...

Comparative Study of the Effects of Antituberculosis Drugs and Antiretroviral Drugs on Cytochrome P450 3A4 and P-Glycoprotein

“…These results might support the interpretation of there being unknown mechanisms operating on DDIs between CFZ and anti-TB drugs, i.e., INH and RIF (39,42,43). In regard to the novel drugs and candidates undergoing preclinical and/or clinical trials, bedaquiline, PA-824, TBA-354, and sutezolid have been reported to be substrates for CYP3A4 (44,45). In particular, PA-824 and TBA-354 have been shown to have weak inhibitory effects on CYP3A4 (46).…”

Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages

“…S1 C). Some 79 Br signal will also have derived from primary metabolites of BDQ, which are also active against Mtb (9). BDQ accumulated heterogeneously in Mtb within macrophages, even between neighbouring bacteria ( Fig.…”

Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers

“…Bedaquiline is metabolized through CYP3A4 (8); thus, the potential for drug-drug interactions with rifamycins exists. In a two-period, sequential-design phase 1 pharmacokinetic study, combining bedaquiline with a different CYP3A4 inducer, efavirenz, an increased clearance of bedaquiline in healthy adult volunteers was noted.…”