Mechanism of Action

Saxagliptin inhibited human dipeptidyl peptidase-4 (DPP-4) enzyme with the IC₅₀=12.8 nM and showed > 100-fold selectivity compared with DPP-8 and DPP-9. ^[1,2]

Inhibition of DPP-4 from cutting and inactivating the incretins (GLP-1 and GIP). ^[3,4,5]

The incretins, especially GLP-1, plays a key role in promoting insulin secretion, increasing insulin receptor sensitivity, delaying gastric emptying, inhibiting food intake and reducing blood glucose regulation. ^[6,7,8]

In Vivo Efficacy

Minimum Effective Dose of Saxagliptin in the treatment of type 2 diabets in animal models:

●    DPP-4 activity inhibition: 0.32 mg/kg (rats) and 0.05 mg/kg (dogs).

●    GLP-1 concentration elevation: 1 mg/kg (rats).

●    Insulin concentration elevation: 1 mg/kg(Zucker (fa/fa) rats).

●    Blood glucose concentration after OGTT: 1.3 mg/kg (Zucker (fa/fa) rats).

●    HbA1c reduction after 2 weeks administration: 10 mg/kg (STZ induced diabetic mice).

●    β cell mass increase: 10 mg/kg (STZ induced diabetic mice).

Absorption of Saxagliptin

Saxagliptin:

●    Saxagliptin had high oral bioavailability in rats (75%), dogs (76%) and monkeys (51%).

●    Saxagliptin was rapidly absorbed, with T_max occurring 0.7 to 1.2 hrs post-dose in non-clinical species and humans.

●    The T_1/2 in rats (2.1 hrs) was similar to humans (2.5 hrs) and slightly lower than dogs (3 hrs) and monkeys (4.4 hrs).

●    The total systemic clearance of saxagliptin ranged from 9.3 mL/min/kg (52% of liver plasma flow) in dogs to 115 mL/min/kg (386% of liver plasma flow) in rats.

●    The Vd_ss was greater than extracellular fluid volume in all of non-clinical species, suggesting extensive extravascular distribution.

●    Saxagliptin had low permeability in Caco-2 cells model (Papp_(A-B): 1.0-1.7×10-6cm/s).

BMS-510849 (an active metabolite):

●    BMS-510849 had poor bioavailability in rats (5%).

●    BMS-510849 had a very small volume of distribution suggesting its distribution was limited to the vascular system.

Distribution of Saxagliptin

Saxagliptin does not bind to proteins in humans and monkeys and only a small protein bound fraction (5%) in rats and dogs and 25% bound in mice. BMS-510849 was only 11% protein bound in monkeys.

In a whole body autoradiography study in rats:

●    The [¹⁴C] saxagliptin-derived radioactivity was extensively distributed in rat tissues. The highest concentrations were found in GI and urinary bladder, which were consistent with the major elimination pathways of saxagliptin. Kidney and liver also showed high radioactivity.

●    The exposure of total radioactivity in brain was lower than that in plasma, indicating limited distribution to the CNS system due to blood-brain barrier.

●    The radioactivity was not quantifiable in any tissues at 168 hrs postdose.

Metabolite of Saxagliptin

The metabolism of saxagliptin by liver microsomes was moderate in all species (33%-79%).

The parent compound was one of the major circulating components in all species and all metabolites observed in humans were also found in the non-clinical species. The exposure of BMS-510849 was generally equal to or greater than saxagliptin in rats (0.2 to 1.2×), dogs (0.7 to 1.7×), monkeys (3.9 to 6.5×) and humans (4 to 7×).

BMS-510849 was the most prominent metabolite of saxagliptin with potent and selective inhibitory activity against the DPP-4 enzyme (Ki=5 μM).

Saxagliptin was metabolized primarily by CYP3A4/5 to BMS-510849.

The metabolites were classified into 1) hydroxylation products 2) direct sulfation products of the parent compound 3) glucuronide conjugates, 4) oxidation products, 5) dehydration products 6) combination of the above products.

Excretion of Saxagliptin

Urine excretion was the main route in dogs and humans, the major component in urine was saxagliptin (33.6% in human), the major component in feces was BMS-510849.

In rats, equal amounts were excreted through urine (saxagliptin) and feces (BMS-510849).

In monkeys, fecal excretion was the main route, the major component in urine and feces was BMS-510849.

Drug-Drug interaction

Neither saxagliptin nor its active metabolite BMS-510849 is induce or inhibit liver CYP enzymes at clinically relevant drug concentration.

Saxagliptin is a weak substrate for p-gp, but BMS-510849 was not.

Saxagliptin and BMS-510849 are not substrates for cellular uptake transporters (i.e. OATP1B1,OATP1B3).

Single-Dose Toxicity

Single dose oral administration of saxagliptin in different species.

●    CD-1 mice MTD: 2000 mg/kg.

●    HSD rats MTD: 2000 mg/kg.

●    Cynomoglus monkeys MTD: 25 mg/kg.

Repeated-Dose Toxicity

Repeated dose oral administration of saxagliptin in different species from 2 to 52 weeks.

●    For mice, NOAEL was 300 mg/kg/day, 361 and 258×MRHD for males and females respectively.

●    For rats, NOAEL was about 2 mg/kg/day, 3 and 8×MRHD for males and females, determined by 26 weeks toxicity study, the target organs of toxicity included the bone marrow, urinary bladder, heart, kidney, liver, lung, ocular accessory gland, spleen, thymus, skeletal muscle and brain; CNS lesion in male rats at high doses.

●    For dogs, NOAEL was about 1 mg/kg/day, 4 and 5×MRHD for males and females, determined by 52 weeks toxicity study, based on findings of epidermal footpad erosion/inflammation and ileocolic congestion at 5 mg/kg.

●    For monkeys, NOAEL was 0.3 mg/kg/day, 2.5 and 1×MRHD for males and females respectively, target organs for toxicity are skin, nephropathy, and immune system related cell suppression.

Safety Pharmacology

Saxagliptin and active metabolites had minimal effects on the cardiovascular safety in animals, but no overt cardiovascular toxicity in human subjects.

Saxagliptin had no adverse effects on respiratory rate, lung sounds or arterial oxygen saturation.

No drug related neurological effects.

Genotoxicity

Saxagliptin: no genotoxicity, but in an earlier clastogenicity assay using primary human lymphocyte, found to be clastogenic at the highest concentration tested (1000 μg/mL) in the absence of S9. The positive human lymphocytes assay appeared to be due to several degradants in the old manufacturing process.

Metabolite BMS-510489: no genotoxicity.

Reproductive and Developmental Toxicity

Rats fertility toxicity: NOAELs were 603 and 776×MRHD for male and female respectively.

Fetal embryonic developmental toxicity: NOAELs were 291 and 152 ×MRHD for rats and rabbits at fetus, respectively;

Postnatal developmental toxicity: NOAEL was 22×MRHD in offspring.

[¹⁴C] Saxagliptin can readily transfer through the placenta, the fetal blood exposure of total radioactivity was approxiamately 50% of the maternal blood exposure.

[¹⁴C] Saxagliptin can transfer to milk, saxagliptin concentration in milk was very similar to maternal blood and plasma, milk: plasma ratio=1.22.

Carcinogenicity

There was no evidence of drug-related increases in the incidence of neoplastic lesions in any dose group in mice or rats carcinogenicity study.

In mouse carcinogenicity study, exposure margins relative to AUC at the 5 mg clinical dose ranged from ~20 to 1000× (low to high dose) for saxagliptin and ~15 to 300× for the active metabolite BMS-510849.

In rat carcinogenicity study, exposure margins relative to AUC at the 5 mg clinical dose ranged from ~50 to 2200× (low to high dose) for saxagliptin and ~3 to 68× for the active metabolite BMS-510849.