Simultaneous oral therapeutic and intravenous ¹4C-microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin.

AIM: To determine the absolute oral bioavailability (F(p.o.) ) of saxagliptin and dapagliflozin using simultaneous intravenous ¹4C-microdose/therapeutic oral dosing (i.v.micro + oraltherap). METHODS: The F(p.o.) values of saxagliptin and dapagliflozin were determined in healthy subjects (n = 7 and 8, respectively) following the concomitant administration of single i.v. micro doses with unlabelled oraltherap doses. Accelerator mass spectrometry and liquid chromatography-tandem mass spectrometry were used to quantify the labelled and unlabelled drug, respectively. RESULTS: The geometric mean point estimates (90% confidence interval) F(p.o) . values for saxagliptin and dapagliflozin were 50% (48, 53%) and 78% (73, 83%), respectively. The i.v.micro had similar pharmacokinetics to oraltherap. CONCLUSIONS: Simultaneous i.v.micro + oraltherap dosing is a valuable tool to assess human absolute bioavailability.

Overcoming bioanalytical challenges in an Onglyza(®) intravenous [(14)C]microdose absolute bioavailability study with accelerator MS.

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. CONCLUSION: 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.