Dipeptidyl peptidase-4 (DPP-4) inhibitor

Resagliptin is a family of chemicals used in the investigation of type 2 diabetes. Repagliptin inhibits the breakdown of GLP-1, hence enhancing the effects of incretin [1].

single-dose, open-label study was conducted in 32 participants categorized by renal function (normal, mild, moderate, severe impairment, and end-stage renal disease (ESRD)) to assess the pharmacokinetics of repagliptin phosphate. All subjects received a single oral dose of 50 mg repagliptin phosphate tablets. [1] Plasma and urine concentrations of the prodrug repagliptin phosphate (SP2086) and its active metabolite repagliptin acid (SP2086 acid) were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. [1] Pharmacokinetic parameters were calculated from plasma concentration-time data using WinNolin 6.1 software. [1]
For SP2086, the time to peak concentration (Tmax) was prolonged with worsening renal function: 1.75±1.21 h (normal), 1.07±0.35 h (mild), 1.50±0.89 h (moderate), 1.67±2.16 h (severe), and 2.42±2.15 h (end-stage renal disease). [1]
The apparent oral clearance (CL/F) of SP2086 decreased significantly with worsening renal function: 30.50±10.70 L/h for normal renal function, 23.50±6.01 L/h for mild renal insufficiency, 12.90±4.34 L/h for moderate renal insufficiency, 6.70±1.55 L/h for severe renal insufficiency, and 3.10±0.48 L/h for end-stage renal disease (ESRD). [1]
The peak concentrations (Cmax) and area under the concentration-time curve (AUC) of both the prodrug (SP2086) and the active metabolite (SP2086 acid) increased with decreasing renal function, while clearance decreased. [1]
The renal clearance (CLr) of the active metabolite SP2086 acid decreased with renal impairment: 289.0±73.7 mL/min for normal renal function and 220.0±51.2 mL/min for mild renal impairment. The cumulative percentage excreted in the urine (Ae%) of SP2086 over 0–96 hours was low, ranging from 0.441% to 4.530% between groups. The Ae% of SP2086 acid was 74.2±14.6% in normal subjects, while it decreased to 34.1±20.0% in patients with ESRD. [1] Compared with subjects with normal renal function, the AUC of SP2086 was 1.44 times, 2.20 times, and 2.83 times higher in patients with moderate, severe, and ESRD, respectively. The AUC of SP2086 acid was 2.32 times, 4.39 times, and 9.28 times higher in each group, respectively. [1]

In a double-blind, phase III, placebo-controlled study of Chinese patients with type 2 diabetes, the incidence of adverse events was 27.78% in the repagliptin 100 mg once daily (qd) group, 20.55% in the repagliptin 50 mg twice daily (bid) group, and 15.97% in the placebo group. [2] The most common adverse events included upper respiratory tract infection, nasopharyngitis, and urinary tract infection. [2] The number of reported hypoglycemic events was 1 in the placebo group, 2 in the repagliptin 100 mg qd group, and 5 in the repagliptin 50 mg bid group. [2]

[1]. Pharmacokinetics of Phosphate Retagliptin Tabletin in Patients with Renal Dysfunction. Sichuan Da Xue Xue Bao Yi Xue Ban. 2018 Jan;49(1):74-80.

[2]. An update on DPP-4 inhibitors in the management of type 2 diabetes. Expert Opin Emerg Drugs. 2016 Dec;21(4):409-419.

Based on the observed increase in systemic exposure (AUC) with declining renal function, it is recommended to adjust the dose of repagliptin phosphate tablets. [1]
The recommended dose is: 100 mg daily for patients with normal renal function and mild renal impairment, 50 mg daily for patients with moderate renal impairment, and 25 mg daily for patients with severe renal impairment. Reagliptin phosphate tablets are not recommended for patients with end-stage renal disease (ESRD). [1]
Reagliptin (SP-2086) is a novel DPP-4 inhibitor developed by Jiangsu Hengrui Medicine for the treatment of type 2 diabetes. [2]
It is a competitive DPP-4 inhibitor belonging to tetrahydroimidozono[1,5-a]pyrazine derivatives, with a structure similar to sitagliptin. [2]
The company has completed two Phase II clinical trials in China to explore the efficacy and safety of the drug as monotherapy and in combination with metformin. [2]
In a double-blind, phase III, placebo-controlled study, researchers evaluated the efficacy and safety of repagliptin in Chinese patients with type 2 diabetes whose blood glucose was poorly controlled by diet and exercise. After a 2-week placebo induction period, 461 patients with HbA1c levels of 7-10.5% were randomized in a 1:1:1 ratio to receive repagliptin 100 mg once daily, 50 mg twice daily, or placebo for 24 weeks. [2]
Compared to the placebo group, both the repagliptin and placebo groups showed significantly greater mean reductions in HbA1c at week 24 (-1.07%, -1.20% vs. -0.34%; p<0.01) and significantly lower fasting blood glucose levels (-0.77 mmol/L, -1.03 mmol/L vs. -0.22 mmol/L; p<0.025). [2]
The proportion of patients achieving a therapeutic glycemic response (HbA1c <7.0%) was significantly higher in the regagliptin 100 mg group. The efficacy of once-daily (44.44%) and twice-daily (50 mg, 53.42%) was superior to placebo (26.39%; p<0.01). [2]
Another phase III clinical trial comparing the efficacy of once-daily or twice-daily regagliptin 50 mg with placebo in combination with metformin has also been completed. [2]
The company withdrew its application to the China National Medical Products Administration in April 2016, but is expected to resubmit it soon. [2]
Regagliptin may be the first DPP-4 inhibitor to be marketed in China by a domestic pharmaceutical company. [2]

C19H21F6N4O7P

562.356826543808

562.105

1256756-88-3

Retagliptin;1174122-54-3

49820554

White to light yellow solid powder

4

15

6

37

748

1

COC(=O)C1=C2CN(CCN2C(=N1)C(F)(F)F)C(=O)C[C@@H](CC3=CC(=C(C=C3F)F)F)N.OP(=O)(O)O

SFNHOWDAQMIJPX-HNCPQSOCSA-N

InChI=1S/C19H18F6N4O3.H3O4P/c1-32-17(31)16-14-8-28(2-3-29(14)18(27-16)19(23,24)25)15(30)6-10(26)4-9-5-12(21)13(22)7-11(9)20;1-5(2,3)4/h5,7,10H,2-4,6,8,26H2,1H3;(H3,1,2,3,4)/t10-;/m1./s1

methyl 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate;phosphoric acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 150 mg/mL (~266.73 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.70 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (3.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)