Amy Qiu Wang

Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses.

Sitagliptin (MK‐0431 [(2R)‐4‐oxo‐4‐(3‐[trifluoromethyl]‐5,6‐dihydro[1,2,4]triazolo[4,3‐a]pyrazin‐7[8H]‐yl)‐1‐(2,4,5‐trifluorophenyl)butan‐2‐amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP‐IV) currently in phase III development for the treatment of type 2 diabetes.

Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males.

AIMS Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. METHODS In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48h post dose and plasma DPP-4 inhibition from 0-24h post dose. The results were compared with historical data from young, healthy non-Japanese males. RESULTS Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50mg resulted in weighted average DPP-4 inhibition from 0-24h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. CONCLUSIONS The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.

PII-49Lack of clinically significant effect of moderate hepatic insufficiency on the pharmacokinetics of MK-0431 (sitagliptin), a dipeptidyl-peptidase-IV (DPP-IV) inhibitor

This study was conducted to evaluate the influence of hepatic insufficiency (HI) on the pharmacokinetics of MK‐0431 (sitagliptin), an orally active, highly selective DPP‐IV inhibitor currently in Phase III development for the treatment of patients with type 2 diabetes.

Determination of a β3-agonist in human plasma by LC/MS/MS with semi-automated 48-well diatomaceous earth plate

Methods for the determination of a beta(3)-agonist (A) in human plasma were developed and compared based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) detection using a turbo ion spray (TIS) interface. Drug and internal standard were isolated from plasma by three sample preparation methods, liquid-liquid extraction, Chem Elut cartridges and 48-well diatomaceous earth plates, that successively improved sample throughput for LC/MS/MS. MS/MS detection was performed on a PE Sciex API 365 tandem mass spectrometer operated in positive ion mode and using multiple reaction monitoring (MRM). The precursor/product ion combinations of m/z 625/607 and 653/515 were used to quantify A and internal standard, respectively, after chromatographic separation of the analytes. Using liquid-liquid extraction and Chem Elut cartridges, the assay concentration range was 0.5-100 ng/ml. Using diatomaceous earth plates, the concentration range of the assay was extended to 0.5-200 ng/ml. For all three assays, the statistics for precision and accuracy is comparable. The assay accuracy ranged from 91-107% and intraday precision as measured by the coefficient of variation (CV) ranged 2-10%. The sample throughput was tripled when the diatomaceous earth plate method was compared with the original liquid-liquid extraction method.

PIII-60Effect of renal insufficiency on the pharmacokinetics of MK-0431 (sitagliptin), a selective dipeptidyl-peptidase-IV (DPP-IV) inhibitor

This study was conducted to evaluate the influence of renal insufficiency (RI) on the pharmacokinetics (PK) of sitagliptin (SIT), a selective DPP‐IV inhibitor in Phase III development for the treatment of type 2 diabetes.

PIII-17Effect of a single cyclosporine a (NEORAL™) dose on the single-dose pharmacokinetics (PK) of sitagliptin (MK-0431), a dipeptidyl peptidase-IV inhibitor (DPP-IV), in healthy male subjects

Sitagliptin (MK‐0431), an orally active, potent and selective DPP‐IV inhibitor being developed for Type 2 diabetes mellitus, is a substrate for p‐glycoprotein (Pgp). High dose cyclosporine A (CSA) was used as a probe Pgp inhibitor to evaluate the effect of potent Pgp inhibition on sitagliptin PK.