12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.

12.2 Pharmacodynamics

In patients with type 2 diabetes mellitus, administration of ONGLYZA inhibits DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Cardiac Electrophysiology

In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator trial using moxifloxacin in 40 healthy subjects, ONGLYZA was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8-times the MRHD).

12.3 Pharmacokinetics

The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%.

No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.

Absorption

The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite.

Effect of Food

Administration with a high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. ONGLYZA may be administered with or without food.

Distribution

The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.

Elimination

Metabolism

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP-4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see Drug Interactions (7.1)].

Excretion

Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of ONGLYZA 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.

Specific Populations

Geriatric Patients

No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.

Male and Female Patients

No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.

Racial or Ethnic Groups

No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 White subjects with 105 subjects of other races (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations.

Patients with Renal Impairment

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage.

The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment with (eGFR 30 to less than 45 mL/min/1.73 m2), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function.

Patients with Hepatic Impairment

In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin. The 10 mg dosage is not an approved dosage. The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful.

Body Mass Index

No dosage adjustment is recommended based on body mass index (BMI) which was not identified as a significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis.

Drug Interaction Studies

In Vitro Assessment of Drug Interactions

The metabolism of saxagliptin is primarily mediated by CYP3A4/5.

In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or inducer of P-gp.

In Vivo Assessment of Drug Interactions

Table 2: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin
Coadministered Drug	Dosage of Coadministered Drug*	Dosage of Saxagliptin*	Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
				AUC†	Cmax
* Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. † AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. ‡ Results exclude one subject. § The plasma DPP4 activity inhibition over a 24-hour dose interval was not affected by rifampin.
No dosing adjustments required for the following:
Metformin	1,000 mg	100 mg	saxagliptin 5-hydroxy saxagliptin	0.98 0.99	0.79 0.88
Glyburide	5 mg	10 mg	saxagliptin 5-hydroxy saxagliptin	0.98 ND	1.08 ND
Dapagliflozin	10 mg single dose	5 mg single dose	saxagliptin 5-hydroxy saxagliptin	↓1% ↑9%	↓7% ↑6%
Pioglitazone‡	45 mg QD for 10 days	10 mg QD for 5 days	saxagliptin 5-hydroxy saxagliptin	1.11 ND	1.11 ND
Digoxin	0.25 mg q6h first day followed by q12h second day followed by QD for 5 days	10 mg QD for 7 days	saxagliptin 5-hydroxy saxagliptin	1.05 1.06	0.99 1.02
Simvastatin	40 mg QD for 8 days	10 mg QD for 4 days	saxagliptin 5-hydroxy saxagliptin	1.12 1.02	1.21 1.08
Diltiazem	360 mg LA QD for 9 days	10 mg	saxagliptin 5-hydroxy saxagliptin	2.09 0.66	1.63 0.57
Rifampin§	600 mg QD for 6 days	5 mg	saxagliptin 5-hydroxy saxagliptin	0.24 1.03	0.47 1.39
Omeprazole	40 mg QD for 5 days	10 mg	saxagliptin 5-hydroxy saxagliptin	1.13 ND	0.98 ND
Aluminum hydroxide + magnesium hydroxide + simethicone	aluminum hydroxide: 2400 mg magnesium hydroxide: 2400 mg simethicone: 240 mg	10 mg	saxagliptin 5-hydroxy saxagliptin	0.97 ND	0.74 ND
Famotidine	40 mg	10 mg	saxagliptin 5-hydroxy saxagliptin	1.03 ND	1.14 ND
Limit ONGLYZA dose to 2.5 mg once daily when coadministered with strong CYP3A4/5 inhibitors [see Drug Interactions (7.1) and Dosage and Administration (2.3)]:
Ketoconazole	200 mg BID for 9 days	100 mg	saxagliptin 5-hydroxy saxagliptin	2.45 0.12	1.62 0.05
Ketoconazole	200 mg BID for 7 days	20 mg	saxagliptin 5-hydroxy saxagliptin	3.67 ND	2.44 ND

ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting

Table 3: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs
Coadministered Drug	Dosage of Coadministered Drug*	Dosage of Saxagliptin*	Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00
Coadministered Drug	Dosage of Coadministered Drug*	Dosage of Saxagliptin*		AUC†	Cmax
* Single dose unless otherwise noted. The 10 mg and 100 mg saxagliptin doses are not approved dosages. † AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. ‡ Results include all subjects.
No dosing adjustments required for the following:
Metformin	1,000 mg	100 mg	metformin	1.20	1.09
Glyburide	5 mg	10 mg	glyburide	1.06	1.16
Pioglitazone‡	45 mg QD for 10 days	10 mg QD for 5 days	pioglitazone hydroxy-pioglitazone	1.08 ND	1.14 ND
Digoxin	0.25 mg q6h first day followed by q12h second day followed by QD for 5 days	10 mg QD for 7 days	digoxin	1.06	1.09
Simvastatin	40 mg QD for 8 days	10 mg QD for 4 days	simvastatin simvastatin acid	1.04 1.16	0.88 1.00
Diltiazem	360 mg LA QD for 9 days	10 mg	diltiazem	1.10	1.16
Ketoconazole	200 mg BID for 9 days	100 mg	ketoconazole	0.87	0.84
Ethinyl estradiol and Norgestimate	ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days	5 mg QD for 21 days	ethinyl estradiol norelgestromin norgestrel	1.07 1.10 1.13	0.98 1.09 1.17

ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting