title: Sensitive and accurate liquid chromatography-tandem mass spectrometry methods for quantitative determination of a novel hepatitis C NS5B inhibitor BMS-791325 and its active metabolite in human plasma and urine.
abstract: BMS-791325 is a novel hepatitis C NS5B inhibitor which is currently in clinical development. To support pharmacokinetic (PK) assessments, sensitive, accurate, precise, and reproducible liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods have been developed and validated for the quantitation of BMS-791325 and its active N-demethyl metabolite (BMS-794712) in human plasma and urine. Plasma and urine samples were extracted with methyl-t-butyl ether followed by an LC-MS/MS analysis which was conducted in a multiple reaction monitoring (MRM) mode for the simultaneous detection of the two analytes in human plasma (0.1-50 ng/mL) and in human urine (5-2500 ng/mL). Intra-run precision (3.0% R.S.D.), inter-run precision (5.3% R.S.D.), and accuracy (±4.7% deviation) from plasma and urine quality control samples provide evidence of the methods accuracy and precision. Selectivity, stability in matrices, extraction recovery, matrix effect on LC-MS detection, and interference of coadministered drugs (famotidine and ritonavir) were all acceptable. Reproducibility of the plasma method was demonstrated by reanalysis of a portion of study samples. The results of cross-validations demonstrated the equivalency of two methods validated in two labs. The plasma method was applied to the analysis of several thousand clinical study samples for PK evaluations of the drug in normal healthy subjects and in patients. The urine method was used in the first in human study to evaluate renal clearance and urinary recovery.
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, United States. Electronic address: hao.jiang@bms.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Tandem Labs, West Trenton, NJ, United States.
authors.forename: Roger
authors.initials: R
authors.lastname: Demers
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, United States.
authors.forename: Hamza
authors.initials: H
authors.lastname: Kandoussi
authors.affiliation: Discovery Chemistry Synthesis, Bristol-Myers Squibb Co., Wallingford, CT, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Burrell
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb Co., Hopewell, NJ, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, United States.
authors.forename: Pathanjali
authors.initials: P
authors.lastname: Kadiyala
authors.affiliation: Tandem Labs, West Trenton, NJ, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Cojocaru
authors.affiliation: Tandem Labs, West Trenton, NJ, United States.
authors.forename: Chanda
authors.initials: C
authors.lastname: Baker
authors.affiliation: Tandem Labs, West Trenton, NJ, United States.
authors.forename: John
authors.initials: J
authors.lastname: Ryan
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, United States.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Aubry
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Arnold
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, United States. Electronic address: jianing.zeng@bms.com.
authors.forename: Jianing
authors.initials: J
authors.lastname: Zeng
mesh_terms: D000998:Antiviral Agents / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology / Q000652:urine*; D001552:Benzazepines / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology / Q000652:urine*; D002853:Chromatography, Liquid / Q000379:methods; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology / Q000652:urine*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: C587012:8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide; D000998:Antiviral Agents; D001552:Benzazepines; D007211:Indoles
keywords: Active metabolite BMS-794712; BMS-791325; Human plasma and urine; LC–MS/MS; Quantitation