title: Overcoming bioanalytical challenges in an Onglyza(®) intravenous [(14)C]microdose absolute bioavailability study with accelerator MS.
abstract: BACKGROUND
  An absolute bioavailability study that utilized an intravenous [(14)C]microdose was conducted for saxagliptin (Onglyza(®)), a marketed drug product for the treatment of Type 2 diabetes mellitus. Concentrations of [(14)C]saxagliptin were determined by accelerator MS (AMS) after protein precipitation, chromatographic separation by UPLC and analyte fraction collection. A series of investigative experiments were conducted to maximize the release of the drug from high-affinity receptors and nonspecific adsorption, and to determine a suitable quantitation range.
  
  
  RESULTS
  A technique-appropriate validation demonstrated the accuracy, precision, specificity, stability and recovery of the AMS methodology across the concentration range of 0.025 to 15.0 dpm/ml (disintegration per minute per milliliter), the equivalent of 1.91-1144 pg/ml. Based on the study sample analysis, the mean absolute bioavailability of saxagliptin was 50% in the eight subjects with a CV of 6.6%. Incurred sample reanalysis data fell well within acceptable limits.
  
  
  CONCLUSIONS
  This study demonstrated that the optimized sample pretreatment and chromatographic separation procedures were critical for the successful implementation of an UPLC plus AMS method for [(14)C]saxagliptin. The use of multiple-point standards are useful, particularly during method development and validation, to evaluate and correct for concentration-dependent recovery, if observed, and to monitor and control process loss and operational variations.
authors.affiliation: Research & Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA. xiaohui.xu@bms.com
authors.forename: Xiaohui Sophia
authors.initials: XS
authors.lastname: Xu
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Dueker
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Christopher
authors.forename: Pete N
authors.initials: PN
authors.lastname: Lohstroh
authors.forename: Chi Fung Anther
authors.initials: CF
authors.lastname: Keung
authors.forename: Kai Kevin
authors.initials: KK
authors.lastname: Cao
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Bonacorsi
authors.forename: Laura
authors.initials: L
authors.lastname: Cojocaru
authors.forename: Jim X
authors.initials: JX
authors.lastname: Shen
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.forename: Bruce
authors.initials: B
authors.lastname: Stouffer
authors.forename: Mark E
authors.initials: ME
authors.lastname: Arnold
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D001682:Biological Availability; D002138:Calibration; D002250:Carbon Radioisotopes / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004151:Dipeptides / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D004341:Drug Evaluation / Q000379:methods; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D002250:Carbon Radioisotopes; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C502994:saxagliptin; D000218:Adamantane