Use of the bromine isotope ratio in HPLC-ICP-MS and HPLC-ESI-MS analysis of a new drug in development

Cuyckens, Filip; Balcaen, Lieve; Wolf, Kenny De; Samber, Björn De; Looveren, Cis Van; Hurkmans, Rob; Vanhaecke, Frank

doi:10.1007/s00216-007-1761-6

Cited by 65 publications

(62 citation statements)

References 24 publications

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“…The two ICP-MS methods described earlier used liquid-liquid extraction and solid-phase extraction and were specifically designed for metabolite profiling and not for PK monitoring (9,10). The run time is very short since the retention time of bedaquiline is 1.9 min.…”

Section: Discussionmentioning

confidence: 99%

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

Alffenaar

Bolhuis

Hateren

et al. 2015

Antimicrob Agents Chemother

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dBedaquiline, a diarylquinoline for the treatment of multidrug-resistant tuberculosis (TB), relies on exposure-dependent killing. As data on drug exposure in specific populations are scarce, pharmacokinetic studies may be of interest. No simple and robust validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported to date. Therefore, a new method using a quadrupole mass spectrometer was developed for analysis of bedaquiline and N-monodesmethyl bedaquiline (M2) in human serum, using deuterated bedaquiline as the internal standard. The calibration curve was linear over a range of 0.05 (lower limit of quantification [LLOQ]) to 6.00 mg/liter for both bedaquiline and M2, with correlation coefficient values of 0.997 and 0.999, respectively. The calculated accuracy ranged from 1.9% to 13.6% for bedaquiline and 2.9% to 8.5% for M2. Within-run precision ranged from 3.0% to 7.2% for bedaquiline and 3.1% to 5.2% for M2, and between-run precision ranged from 0.0% to 4.3% for bedaquiline and 0.0% to 4.6% for M2. Evaluation of serum concentrations in a patient receiving bedaquiline showed high levels at the end of treatment, reflecting accumulation of the drug. More observational pharmacokinetic data are needed to relate altered drug concentrations to clinical outcome or adverse drug effects. A simple LC-MS/MS method to quantify bedaquiline and M2 levels in human serum using a deuterated internal standard has been validated. This method can be used in clinical studies and daily practice. Bedaquiline is a diarylquinoline and was approved by the United States Food and Drug Administration (FDA) in 2012 under the accelerated-approval program. This drug is indicated for treatment of multidrug-resistant pulmonary tuberculosis (MDR-TB) in combination with other active anti-TB drugs in adults without other treatment options (1). This new anti-TB drug, formally known as TMC207, showed exposure-dependent killing of Mycobacterium tuberculosis (2, 3). The drug is metabolized by cytochrome P 450 enzyme 3A4 (CYP3A4) to its 5-foldless-active metabolite N-monodesmethyl bedaquiline (M2) (4).Bedaquiline therapy is started in a loading dose of 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks. This dosing regimen was chosen because pharmacokinetics (PK) modeling predicted gradual accumulation in plasma and tissues (4).At this time, little data on PK in patients with advanced MDR-TB or suffering from comorbidities are available apart from the data that were collected in the clinical studies (4). However, variability in the PK of antituberculosis drugs is considerable and altered drug exposure may translate to variations in clinical outcomes (5, 6). Clearly, there is a need for more-descriptive (population) PK studies on bedaquiline to determine predictors of exposure, drug-drug interaction (7), and PK-pharmacodynamics (PD) relationships. The World Health Organization has released a guide for the use of bedaquiline and encourages additional evaluation of this new drug (8).As bedaquilin...

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Section: Discussionmentioning

confidence: 99%

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

Alffenaar

Bolhuis

Hateren

et al. 2015

Antimicrob Agents Chemother

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“…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-didesmethyl BDQ, and two hydroxyl metabolites, are mainly excreted via feces (Cuyckens et al, 2008;Meermann et al, 2012). However, limited information is available for bioactivation pathways of BDQ that may be related to BDQ toxicity.…”

Section: Introductionmentioning

confidence: 99%

Bedaquiline Metabolism: Enzymes and Novel Metabolites

Liu

et al. 2014

Drug Metabolism and Disposition

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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...

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“…The LTQOrbitrap has also been used to analyze intact small (3-10 kDa) (Bredehöft, Schänzer, & Thevis, 2008;Thevis et al, 2006a;Thevis, Thomas, & Schänzer, 2008b), medium (10-25 kDa) (Macek et al, 2006;Waanders, Hanke, & Mann, 2007) and large ($150 kDa) (Zhang & Shah, 2007) proteins where the MS n capability of the LIT coupled with the high performance features of the orbitrap can facilitate unambiguous determination of the charge states of fragment ions, as well as identification of PTMs by database searching. The high performance attributes of this hybrid mass spectrometer have also found applications in environmental chemistry (Barceló & Petrovic, 2007;Krauss & Hollender, 2008), drug and metabolite analysis (Breitling, Pitt, & Barrett, 2006;Cuyckens et al, 2008;Ding et al, 2007;Karu et al, 2007;Li et al, 2007a;Lim et al, 2007Lim et al, , 2008Madalinski et al, 2008;Nielen et al, 2007;Peterman et al, 2006;Ruan et al, 2008;Thevis et al, 2005;Thevis, Kamber, & Schänzer, 2006b;Thevis, Krug, & Schänzer, 2006c;Thevis et al, 2006dThevis et al, ,e, 2007aThevis et al, , 2008aZhu et al, 2007), lipidomics (Davis et al, 2008;Ejsing et al, 2006;Schwudke et al, 2007;Silipo et al, 2008), small-molecule (Chen et al, 2007b) and reaction product (Jamin et al, 2007) identification, as well as molecular structure characterization using hydrogen/deuterium exchange measurements (Chen et al, 2007a;...…”

Section: Introductionmentioning

confidence: 99%

Orbitrap mass spectrometry: Instrumentation, ion motion and applications

Perry

Cooks

Noll

2008

Mass Spectrometry Reviews

406

290

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Since its introduction, the orbitrap has proven to be a robust mass analyzer that can routinely deliver high resolving power and mass accuracy. Unlike conventional ion traps such as the Paul and Penning traps, the orbitrap uses only electrostatic fields to confine and to analyze injected ion populations. In addition, its relatively low cost, simple design and high space‐charge capacity make it suitable for tackling complex scientific problems in which high performance is required. This review begins with a brief account of the set of inventions that led to the orbitrap, followed by a qualitative description of ion capture, ion motion in the trap and modes of detection. Various orbitrap instruments, including the commercially available linear ion trap–orbitrap hybrid mass spectrometers, are also discussed with emphasis on the different methods used to inject ions into the trap. Figures of merit such as resolving power, mass accuracy, dynamic range and sensitivity of each type of instrument are compared. In addition, experimental techniques that allow mass‐selective manipulation of the motion of confined ions and their potential application in tandem mass spectrometry in the orbitrap are described. Finally, some specific applications are reviewed to illustrate the performance and versatility of the orbitrap mass spectrometers. © 2008 Wiley Periodicals, Inc., Mass Spec Rev 27: 661–699, 2008

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Use of the bromine isotope ratio in HPLC-ICP-MS and HPLC-ESI-MS analysis of a new drug in development

Cited by 65 publications

References 24 publications

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

Bedaquiline Metabolism: Enzymes and Novel Metabolites

Orbitrap mass spectrometry: Instrumentation, ion motion and applications

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