Trelagliptin Succinate

Trelagliptin succinate was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on March 26, 2015. It was developed and marketed as Zafatek® by Takeda in Japan.

Trelagliptin succinate is a once-weekly dipeptidyl peptidase-IV (DPP-4) inhibitor. It controls blood glucose levels by selectively and continually inhibiting DPP-4, an enzyme that causes the inactivation of glucagon-like peptide-1 and glucagon-dependent insulinotropic polypeptide, incretin hormones that play an important role in blood glucose regulation. The inhibition of DPP-4 increases insulin secretion depending on blood glucose concentration, thereby controlling blood glucose levels. It is indicated for the treatment of type 2 diabetes.

Zafatek® is available as tablet for oral use, containing 50 or 100 mg of free Trelagliptin. The recommended dose is 100 mg of trelagliptin orally once a week for adults. 

Index：

General Information

Update Date：2016-03-22

Drug Name：
Trelagliptin Succinate
Research Code：
SYR-472
Trade Name：
Zafatek®
MOA：
Dipeptidyl peptidase-4 (DPP-4) inhibitor
Indication：
Type 2 diabetes
Status：
Approved
Company：
Takeda (Originator)
Sales：
ATC Code：
A10BH
Approved Countries or Area

Update Date：2015-08-27

Approval Date Approval Type Trade Name Indication Dosage Form Strength Company Review Classification
2015-03-26 Marketing approval Zafatek Type 2 diabetes Tablet Eq. 100 mg/50 mg Trelagliptin Takeda
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Chemical Structure

Update Date：2015-09-28

Molecular Weight 475.47
Formula C18H20FN5O2 ● C4H6O4
CAS No. 865759-25-7 (Trelagliptin);
1029877-94-8 (Trelagliptin Succinate);
Chemical Name (R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile succinate
Trelagliptin （Free Acid/Base）Parameters：
MW HD HA FRB* PSA* cLogP*
357.38 2 7 4 93.7 1.450±0.494
*：Calculated by ACD/Labs software V11.02.
Related Patents

Update Date：2015-11-30

No. Major Technical Classification Publication No. Patent No. Legal Status Filling Date Estimated Expiry Date
1 Formula CN1926128A Refusal 2004/12/15
2 Formula CN102079743A Examination 2004/12/15
3 Preparation CN102127053A Examination 2004/12/15
4 Formula CN102127057A Refusal 2004/12/15
5 Formula CN102134229A Examination 2004/12/15
6 Formula CN102134230A Examination 2004/12/15
7 Preparation CN102134231A Examination 2004/12/15
8 Formula CN102140090A Withdrawn 2004/12/15
9 Formulation CN101374523A CN101374523B Granted 2006/9/13 2026/9/13
10 Preparation CN101360723A Refusal 2006/9/15
11 Formula CN102675221A Examination 2006/9/15
12 Indication CN101389339A CN101389339B Granted 2006/12/27 2026/12/27
13 Indication CN101616673A Refusal 2007/9/11
14 Indication CN103211819A Examination 2007/9/11
15 Crystal CN101573351A CN101573351B Granted 2007/11/29 2027/11/29
16 Indication CN101778633A Refusal 2008/3/12
17 Indication CN103142600A Examination 2008/3/12
18 Formulation CN102548556A Withdrawn 2010/7/27
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Synthesis & Impurities

Update Date：2016-02-21


1. WO2007035629A2 / US8222411B2.

2. WO2005095381A1 / US7781584B2.

3. WO2007112368A1 / US2010029941A1.

4. WO2008067465A1 / US8084605B2.

5. WO2008033851A2 / US2011077402A1.

6. WO2012118180A1 / US2014023708A1.


1. CN103030631A.


1. WO2015137496A1.

1
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity A C18H20FN5O2 357.38
2
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity B C31H28F2N8O4 614.6
3
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity C C23H24FN7O4 481.48
4
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity D C26H24F2N6O2 490.5
5
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity E C40H42F2N10O6 796.82
6
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity F C18H20FN5O2 357.38
7
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity G C17H18FN5O2 343.36
8
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity H C18H22FN5O3 375.4
9
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity I C18H21FN4O4 376.38
10
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity J C18H21N5O2 339.39 850649-61-5
11
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity K C23H31N7O2 437.54
12
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity L C22H24FN5O5 457.45
13
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity M C13H9ClFN3O2 293.68
14
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity N C5H6N2O3 142.11 2565-47-1
15
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity O C5H5ClN2O2 160.56 31737-09-4
16
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity P C8H6FN 135.14 147754-12-9
17
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity Q C7H6BrF 189.02 452-63-1
18
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity R C7H7F 110.13 352-70-5
19
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity S C7H5Br2F 267.92 112399-50-5
20
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity T C5H5ClN2O2 160.56 4318-56-3
21
Impurity Name: Molecular Formula: Molecular Weight: CAS No.:
Trelagliptin Impurity U C8H5BrFN 214.03 421552-12-7
Non-clinical Pharmacology

Update Date：2016-06-16

Mechanism of Action

●    Trelagliptin is a selective, competitive and reversible inhibitor of dipeptidyl peptidase-4 (DPP-4) (Ki=1.5 nM, dissociation t1/2= 29 min).

●    By specific inhibition of DDP-4 activity (IC50=1.3 nM for human recombinant ddp-4), trelagliptin prevented the degradation of incretin (GLP-1 and GIP) and prolonged half-life of active forms, resulting in release of insulin and decrease of blood glucose post prandial.

●    Trelagliptin was highly selective DDP-4 inhibitor, which showed >10,000 fold lower inhibitory potency against the other peptidases: DPP-8, DPP-9, DPP-II, PEP or FAPα.

●    Trelagliptin showed no significantly inhibition up to 10 μM in a screening against a panel of 47 enzymes and 79 receptors, ion channels and transporter in vitro.

[1]. Japan, PMDA.

In Vivo Efficacy

●    In N-STZ-1.5 non-obese T2DM rats:

v    The effect of single dose on OGTT:

Ø    Inhibited plasma DPP-4 activity and increased plasma insulin at 0.03 mg/kg.

Ø    Significantly decreased AUC of glucose and increased plasma active GLP-1.

v    Single dose compared with alogliptin: Lower dosing with the same effect.

●    In Wistar fatty rats (obese T2DM):

v    Significantly reduced AUC of glucose of OGTT at 0.03 mg/kg;

v    Dose-dependently inhibited the DPP-4 activity and increased plasma insulin.

●    Administration in food for 3 days in ob/ob mice:

v    Dose-dependently effect on the inhibition of plasma dpp-4 activity and increase of plasma active GLP-1, the minimum effect dose was 0.001% (~1.6 mg/kg/day).

v    0.03% (~50.3 mg/kg/day): 90% inhibition of plasma DPP-4 activity and 4.8-fold increase of plasma active GLP-1.

●    Administration in food for 4 weeks in ob/ob mice: Mice with food containing 0.03% (51.9 mg/kg/day) trelagliptin:

v    HbA1c decreased for 0.9%.

v    Insulin: 1.9-fold increase in plasma and 1.8-fold increase in pancreas.

[1]. Japan, PMDA.

Non-clinical Pharmacokinetics

Update Date：2016-06-16

Absorption

●    The increase in Cmax and AUC of trelagliptin and M-I in the dose range of 3 to 30 mg/kg appeared to be dose-proportional in rats. Trelagliptin produced a nonlinear PK profile over 3-30 mg/kg in dogs due to saturation of metabolizing enzymes. The increase in Cmax and AUCinf of trelagliptin was dose dependent in the dose range of 3.125 to 800 mg in humans.

●    Trelagliptin had good absorption in rats (50.3%) and dogs (129.8%). 

●    Trelagliptin was absorbed rapidly (Tmax =1.00 -1.50 hrs) in humans and in rats (1.0-2.3 hr), but was absorbed slowly in dogs (1.0-6.5 hrs).

●    The half-life of trelagliptin in humans (38.44 - 54.6 hrs) was longer than them in rats (3.3-5.2 hrs), and dogs (3.5-6.2 hrs).

●    The clearance of trelagliptin in humans (10.5 - 16.2 L/hr) was lower than liver blood flow.

●    The permeability of trelagliptin was low with the Papp(A→B) =1.53-2.00×10-6cm/s in Caco-2 cells model.

[1]. Japan, PMDA.

Distribution

●    Trelagliptin exhibited low in humans (22.1-27.6%), rats (24.1-54.7 %), dogs (22.8-25.2 %) , the binding was concentration-dependent in the range of 0.1-10 μg/mL in rats. The blood cell partition (%) was low in humans (49.2-55.0%), rats (31. 2-49.9%), dogs (51.4 -59.0 %) suggesting partial penetration into red blood cells.

●    Male rats following a single oral administration:

v    The highest concentration of tissues reached at 1 and 6 hrs.

v    Radioactivity levels in most tissues consistently greater than those observed in blood. The high concentration tissues were intestine followed by kidney, stomach, liver, lung, and adrenal. Radioactivity in brain was below those observed in blood.

v    In pigment rats, some accumulation was observed in sclera. Trelagliptin and it metabolite M-I had melanin affinity.

v    The radioactivity in tissues eliminated quickly without accumulation.

[1]. Japan, PMDA.

Metabolism

●    The metabolism was stable in rat, dog and human hepatocytes.

●    No unique metabolite was observed in human.

●    In rat plasma, the main component was trelagliptin and the main metabolites of trelagliptin was N-demethylation (M-I), in dog plasma, the main component was M-I. In rat sclera, the main component was trelagliptin. In human plasma, the major component was trelagliptin.

●    CYP2D6 was the major metabolic enzyme of M-I, CYP3A4 was the major metabolic enzyme of other metabolites.

●    The major metabolite (M-I) was an active metabolite, but DPP-4 inhibition activity was lower than trelagliptin.

●    In rat and dog plasma, no chiral inversion occurred.

[1]. Japan, PMDA.

 Excretion

●    The predominant elimination route of trelagliptin was via urine in humans and dogs. The predominant elimination route of trelagliptin was via feces in rats. The major component was parent in rat urine but M-I in dog urine.

●    In bile duct cannulated rats, the biliary excretion of trelagliptin was 20.0% after a single duodenum administration.

●    In rat the enterohepatic circulation was observed.

[1]. Japan, PMDA.

Drug-Drug Interaction

●    Trelagliptin was a metabolism-based inhibitor of CYP3A4 (IC50=28 μM) and CYP3A5 (IC50=12 μM).

●    Trelagliptin was not an inducer of CYP1A2, CYP2B6 and CYP3A4.

●    Trelagliptin was an inhibitor of OCT2 (IC50=55.9 μM), but was not inhibitors of BCRP, OATP1Bl, OATP1B3, OAT1 and OAT3.

●    Trelagliptin was a substrate of P-gp and was a weak P-gp inhibitor.

[1]. Japan, PMDA.

Non-clinical Toxicology

Update Date：2016-06-16

Single Dose Toxicity

●    Single oral administration of trelagliptin in different species:

●    Rats MTD: 2000 mg/kg.

●    Dogs MTD: 2000 mg/kg.

[1]. Japan, PMDA.

Repeated Dose Toxicity

●    Repeated dose toxicity studies were performed in rats (up to 26 weeks), and dogs (up to 39 weeks).

●    For rats, the NOAEL was 250 mg/kg/day, which was 41×MRHD, determined by 26-week toxicity study. Target organ of toxicity was liver and hematopoiesis.

●    For dogs, the NOAEL was 100 mg/kg/day, which was 39 ×MRHD, determined by 39-week toxicity study. No drug treatment related toxicity.

[1]. Japan, PMDA.

Safety Pharmacology

●    No effects on central nervous system, cardiovascular system and respiratory system.

●    Cardiovascular system: in vitro study (hERG assay) %inhibition was 6.5% at 3 μM and 17.4% at 30 μM.

[1]. Japan, PMDA.

Genotoxicity

●    There was no apparent genetic toxicology for trelagliptin.

[1]. Japan, PMDA.

Reproductive and Developmental Toxicity

●    Fertility and early embryonic development: the NOAELs were ≥1000 mg/kg/day for parental and early embryo-fetal in rats.

●    Embryo-fetal development: in rats, the NOAELs were 300 mg/kg/day for maternal and development; in rabbits, the NOAELs were 100 and 250 mg/kg/day for maternal and development, respectively.

●    In the pre- and postnatal toxicity studies in rats, the NOAELs were 300 mg/kg/day for F0 and F1.

●    Trelagliptin-related radioactivity is able to cross the placenta in rats, the plasma concentration ratio of fetus/maternal = 0.3.

●    Trelagliptin secreted into rat milk, milk/ plasma Cmax ratio=1.2; milk/ plasma AUC0-48 hr ratio=1.1.

[1]. Japan, PMDA.

Carcinogenicity

●    For mice, NOAELs were<100 and 100 mg/kg/day for males and females, respectively, which were 6 and 8 × MRHD for males and females, respectively.

●    For rats, NOAEL was 75 and 50 mg/kg/day for males and females, which was 17 and 9 × MRHD for males and females, respectively.

●    There were no treatment related tumors.

[1]. Japan, PMDA.