ONGLYZA (Page 5 of 14)

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.

Gender

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.

Geriatric

No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean C_max 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.

Race and Ethnicity

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

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 dipeptidyl peptidase-4 (DPP4) activity inhibition over a 24-hour dose interval was not affected by rifampin.
No dosing adjustments required for the following:
Metformin	1000 mg	100 mg	saxagliptin5-hydroxy saxagliptin	0.980.99	0.790.88
Glyburide	5 mg	10 mg	saxagliptin5-hydroxy saxagliptin	0.98ND	1.08ND
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	saxagliptin5-hydroxy saxagliptin	1.11ND	1.11ND
Digoxin	0.25 mg q6h first day followed by q12h second day followed by QD for5 days	10 mg QD for 7 days	saxagliptin5-hydroxy saxagliptin	1.051.06	0.991.02
Simvastatin	40 mg QD for 8 days	10 mg QD for 4 days	saxagliptin5-hydroxy saxagliptin	1.121.02	1.211.08
Diltiazem	360 mg LA QD for 9 days	10 mg	saxagliptin5-hydroxy saxagliptin	2.090.66	1.630.57
Rifampin §	600 mg QD for 6 days	5 mg	saxagliptin5-hydroxy saxagliptin	0.241.03	0.471.39
Omeprazole	40 mg QD for 5 days	10 mg	saxagliptin5-hydroxy saxagliptin	1.13ND	0.98ND
Aluminum hydroxide + magnesium hydroxide + simethicone	aluminum hydroxide:2400 mgmagnesium hydroxide:2400 mgsimethicone: 240 mg	10 mg	saxagliptin5-hydroxy saxagliptin	0.97ND	0.74ND
Famotidine	40 mg	10 mg	saxagliptin5-hydroxy saxagliptin	1.03ND	1.14ND
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	saxagliptin5-hydroxy saxagliptin	2.450.12	1.620.05
Ketoconazole	200 mg BID for 7 days	20 mg	saxagliptin5-hydroxy saxagliptin	3.67ND	2.44ND

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

				AUC *	Cmax
* AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. † Single dose unless otherwise noted. The 10 mg and 100 mg saxagliptin doses are not approved dosages. ‡ Results include all subjects.
Coadministered Drug	Dosage of Coadministered Drug †	Dosage of Saxagliptin †	Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00
No dosing adjustments required for the following:
Metformin	1000 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	pioglitazonehydroxy-pioglitazone	1.08ND	1.14ND
Digoxin	0.25 mg q6h first day followed by q12h second day followed by QD for5 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	simvastatinsimvastatin acid	1.041.16	0.881.00
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 estradiolnorelgestrominnorgestrel	1.071.101.13	0.981.091.17

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