title: Determination of bedaquiline in human serum using liquid chromatography-tandem mass spectrometry.
abstract: Bedaquiline, 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.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands j.w.c.alffenaar@umcg.nl.
authors.forename: Jan-Willem C
authors.initials: JW
authors.lastname: Alffenaar
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bolhuis
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Kai
authors.initials: K
authors.lastname: van Hateren
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Sturkenboom
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
authors.forename: Onno
authors.initials: O
authors.lastname: Akkerman
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
authors.forename: Wiel
authors.initials: W
authors.lastname: de Lange
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Ben
authors.initials: B
authors.lastname: Greijdanus
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands.
authors.forename: Tjip
authors.initials: T
authors.lastname: van der Werf
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands University of Groningen, University Center of Pharmacy, Section of Pharmacokinetics, Toxicology and Targeting, Groningen, The Netherlands.
authors.forename: Daan
authors.initials: D
authors.lastname: Touw
mesh_terms: D002853:Chromatography, Liquid / Q000379:methods*; D064687:Diarylquinolines / Q000097:blood* / Q000627:therapeutic use; D006801:Humans; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*; D018088:Tuberculosis, Multidrug-Resistant / Q000097:blood* / Q000188:drug therapy
chemical_list: D064687:Diarylquinolines; C493870:bedaquiline