Clinical Pharmacokinetic Study Of Retagliptin Phosphate Tablets In Volunteers Of Renal Insufficiency

Retagliptin phosphate tablets were designed for the treatment of type 2 diabetes,which are the "me-too" drugs of sitagliptin phosphate of Merck.After administration,retagliptin phosphate was metabolized to retagliptin rapidly.Then retagliptin was metabolized to M1.Ml was the active metabolite.Retagliptin and M1 were the inhibitors of dipeptidyl peptidase-4(DPP-4),the enzyme responsible for inactivating incretin hormones(GLP-1 and GIP).The half-life of GLP-1 and GIP extended when DPP-4 enzyme was inhibited.Incretins are essential for reducing the concentration of glucose in plasma by stimulating insulin secretion.Diabetes is a disease of metabolic disorder.Diabetes can cause renal insufficiency.The dosage needs to adjust when retagliptin phosphate tablets used to treatment diabetes with renal insufficiency.There are limited reports of retagliptin phosphate tablets about pharmacokinetic study.The purpose of the study is to develop a high-performance liquid chromatography-tandem mass spectrometry(LC-MS/MS)method to simultaneously quantify retagliptin and M1 in plasma and urine.The method was applied to clinical pharmacokinetic study of retagliptin phosphate tablets.Method:The biological samples were treated with methanol to precipitate protein,and then the supernatant was diluted with water.Retagliptin,Ml and sitagliptin as internal standard(I.S.)were separated on a Agilent Eclipse Plus C18 column using methanol-0.1%formic acid solution as mobile phase.Electrospray ionization(ESI)source was applied and operated in the positive ion mode.Multiple reaction monitoring(MRM)mode were used to quantify retagliptin,M1 and sitagliptin.The standard calibration curves for retagliptin and Ml were linear over the concentration ranges of 0.100-100 ng/mL and 0.300-500 ng/mL in human plasma,respectively.The standard calibration curves for retagliptin and M1 were linear over the concentration ranges of 5.00-5000 ng/mL and 10.0-10000 ng/mL in human urine,respectively.The validation of method is fully progressed according with China Food and Drug Administration(CFDA)guidance.The methods were used to determine the concentration of retagliptin and Ml in plasma or urine samples after a single oral dose of 50 mg retagliptin phosphate tablets to volunteers of renal insufficiency.Results:Methods for the determination of retagliptin and Ml in plasma or urine samples based on liquid chromatography-tandem mass spectrometry(LC-MS/MS)have been developed and validated.The quantitative methods,which is simple,rapid,sensitive,accurate,precise,reliable,can be applied to the clinical pharmacokinetic study of retagliptin phosphate tablets.After administration of 50 mg retagliptin phosphate tablets,blood samples and urine samples were collected.The pharmacokinetic parameters of volunteers with renal insufficiency were different from the pharmacokinetic parameters of healthy volunteers.After administration,AUC0-? of retagliptin and Ml were 176 ± 26.5 ng/mL·h and 1800 ± 567 ng/mL·h in the healthy volunteers,respectively;Cmax were 20.5 ±7.14 ng/mL and 389 ± 102 ng/mL respectively;t1/2 were 13.4 ± 1.90 h and 12.8 ± 3.90,respectively.After administration,AUC0-? of retagliptin and Ml were 189 ± 43.1 ng/mL·h and 2370 ± 425 ng/mL·h in volunteers with mild renal insufficiency,respectively;Cmax were 31.7±6.63 ng/mL and 588 ± 155 ng/mL,respectively,t1/2 were 15.2 ± 3.50 h and 15.8 ± 5.30h,respectively.After administration,AUC0-? of retagliptin and Ml were 254 ± 80.1 ng/mL·h and 4165 ± 1147 ng/mL·h in volunteers with moderate renal insufficiency,respectively;Cmax were 25.8±6.01 ng/mL and 642 ± 132 ng/mL,respectively;t1/2 were 21.8 ±4.10 h and 18.5±3.90,respectively.After administration,AUC0-? of retagliptin and Ml were 389 ± 72.0 ng/mL-h and 7877 ±2329 ng/mL·h in volunteers with severe renal insufficiency,respectively;Cmax were 42.7 ± 15.6 ng/mL and 1034 ± 312 ng/mL,respectively;t1/2 were 12.6 ± 7.70 h and 17.1 ± 7.00 h,respectively.After administration,AUC0-? of retagliptin and Ml were 501 ± 135 ng/mL·h and 16669 ± 2827 ng/mL·h in volunteers with ESRD,respectively.Cmax were 38.2 ± 13.2 ng/mL and 1275 ± 347 ng/mL,respectively;t1/2 were 15.4 ±3.40 h and 14.0 ± 4.70 h,respectively.Because of renal failure,AUC,Cmax increased,and t1/2 didn't changed significantly.After administration retagliptin phosphate tablets,the total urinary excretive ratios were:78.2 ± 15.8%(the healthy volunteers),78.6 ± 14.6%(volunteers with mild renal insufficiency),61.3 ± 23.3%(volunteers with moderate renal insufficiency),64.4 ± 14.3%(volunteers with severe renal insufficiency),and 34.3 ± 20.2%(volunteers with ESRD),respectively.The excretion of drugs decreased because of renal failure.The MRT increased and the cumulative excretion ratios decreased,significantly.