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Quantitative determination of BMS‐378806 in human plasma and urine by high‐performance liquid chromatography/tandem mass spectrometry
Author(s) -
Xue Y.J.,
Yan JingHe,
Arnold Mark,
Grasela Dennis,
Unger Steve
Publication year - 2007
Publication title -
journal of separation science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.72
H-Index - 102
eISSN - 1615-9314
pISSN - 1615-9306
DOI - 10.1002/jssc.200600499
Subject(s) - chromatography , chemistry , pharmacokinetics , formic acid , urine , electrospray ionization , analyte , tandem mass spectrometry , quantitative analysis (chemistry) , calibration curve , high performance liquid chromatography , mass spectrometry , liquid chromatography–mass spectrometry , detection limit , pharmacology , medicine , biochemistry
BMS‐378806 is a human immunodeficiency virus (HIV) entry inhibitor that is being developed for the oral treatment of HIV infection. Human plasma and urine LC/MS/MS methods have been developed and validated for the quantitation of BMS‐378806. For human plasma method, methyl t ‐butyl ether was used to extract BMS‐378806 from plasma in a 96‐well format, and the organic layers were dried down and then reconstituted for the injection, while a dilute‐and‐shoot approach was used for human urine method in a 96‐well format. Chromatographic separation was achieved isocratically on a Phenomenex C18 (2) Luna column (2×50 mm 2 , 5 μm). The mobile phase contained 60:40 v/v of 0.1% formic acid in water and ACN. Detection was by positive ion electrospray MS/MS. The standard curves ranged from 1.25 to 1000 ng/mL for the plasma assay and from 10 to 5000 ng/mL for the urine assay. The curves were fitted to a 1/ x 2 weighted quadratic regression model for both methods. The validation results demonstrated that both methods had satisfactory precision and accuracy across the calibration ranges. The methods were applied to the analysis of human plasma and urine samples from a single ascending dose clinical study to assess the pharmacokinetics of the drug. The pharmacokinetic analysis results indicated the absorption and disposition of the drug was rapid. The systemic exposure of BMS‐378806 was generally dose proportional among the doses from 100 to 1200 mg, but not dose proportional to 1600 mg. There were modest increases in the systemic exposure when the drug was given with food or given as a solution formulation. Renal excretion was not a substantial elimination pathway of the drug. BMS‐378806 was safe and well tolerated over a dose range of 100–1600 mg administered as a single oral dose.