Final ProgramCPSA 2011
Science and Technology Coming Together to Make a Difference
October 3 - 6, 2011
Bucks County Sheraton Hotel
Langhorne, PA
Poster Abstract #03
Achieving Regulatory Approval: Overcoming Bioanalytical Challenges in an Onglyza™ Micro-tracer Absolute Bioavailability Study with Accelerator Mass Spectrometry
1) Research & Development, Bristol-Myers Squibb, Princeton, New Jersey 08543 USA; 2) Vitalea Sciences, Inc, Davis, CA 95618 USA; 3) roongtav2@embarqmail.com; 4) Tandem Labs, West Trenton, NJ 08440 USA
Characterization of absolute oral bioavailability (BA) is useful for oral drug development and is a requirement of some Health Authorities. Here we present results from an absolute BA study in which a microdose of intravenous (IV) [14C]saxagliptin was administered concomitantly with an efficacious oral dose of saxagliptin (BMS-477118, Onlgyza™). Orally administered saxagliptin was measured in plasma using a validated protein precipitation method with LC-MS/MS detection. Intravenously administered [14C]saxagliptin was determined by Accelerator Mass Spectrometry (AMS) after protein precipitation, UPLC-fractionation, and graphitization. The graphitiziation process results in aloss of structural information, therefore, chromatographic separation to fully resolve a drug from its metabolites is required to achieve assay specificity. Many practices involved in LC-MS/MS method development and validation are less appropriate for the AMS method. Challenges related to suitable sample preparation methodology for AMS and their solutions will be presented. A technique-appropriate validation was conducted that fully demonstrated the accuracy, precision, stability, specificity and recovery of the AMS method across the concentration range of 0.025 to 15.0 DPM/mL (equivalent to 1.91 to 1144 pg/mL). The raw AMS measurement, 14C/C ratio, expressed as fMC (fraction Modern Carbon) and known DPM/mL of [14C]saxagliptin standards, were used to construct a weighted (1/y2) least-squares, linear regression model and used to predict the concentration of unknowns. The absolute bioavailability of saxagliptin was calculated at ~50%. Pharmacokinetic results indicated good agreement in the terminal phase half-life values between the intravenous and oral routes demonstrating that the IV radioactive microdose provides a sound approach to determine absolute bioavailability.
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