CLINICAL PHARMACOLOGY
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 dipeptidyl
peptidase-4 (DPP4) enzyme within minutes. GLP-1 also lowers glucagon secretion
from pancreatic alpha cells, reducing hepatic glucose production. In patients
with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin
response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 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.
Pharmacodynamics
In patients with type 2 diabetes mellitus,
administration of ONGLYZA inhibits DPP4 enzyme activity for a 24-hour period.
After an oral glucose load or a meal, this DPP4 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 study 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).
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 •h/mL and 214 •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. 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.
Metabolism
The metabolism of saxagliptin is
primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite
of saxagliptin is also a DPP4 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)
.]
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
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 (N=8 per group)
compared to subjects with normal renal function. The study included patients
with renal impairment classified on the basis of creatinine clearance as mild
(>50 to ≤80 mL/min), moderate (30 to ≤50 mL/min), and severe (<30 mL/min),
as well as patients with end-stage renal disease on hemodialysis. Creatinine
clearance was estimated from serum creatinine based on the Cockcroft-Gault
formula:
| CrCl = |
[140 — age (years)] x weight (kg) |
{x 0.85 for female patients} |
| |
[72 x serum creatinine (mg/dL)] |
|
The degree of renal impairment did not affect the Cmax of
saxagliptin or its active metabolite. In subjects with mild renal impairment,
the AUC values of saxagliptin and its active metabolite were 20% and 70%
higher, respectively, than AUC values in subjects with normal renal function.
Because increases of this magnitude are not considered to be clinically relevant,
dosage adjustment in patients with mild renal impairment is not recommended.
In subjects with moderate or severe renal impairment, the AUC values of saxagliptin
and its active metabolite were up to 2.1- and 4.5-fold higher, respectively,
than AUC values in subjects with normal renal function. To achieve plasma
exposures of saxagliptin and its active metabolite similar to those in patients
with normal renal function, the recommended dose is 2.5 mg once daily in patients
with moderate and severe renal impairment, as well as in patients with end-stage
renal disease requiring hemodialysis. Saxagliptin is removed by hemodialysis.
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 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. No dosage
adjustment is recommended for patients with hepatic impairment.
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 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.
Pediatric
Studies characterizing the pharmacokinetics
of saxagliptin in pediatric patients have not been performed.
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-Drug Interactions
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.
The in
vitro protein binding of saxagliptin and its active metabolite in
human serum is negligible. Thus, protein binding would not have a meaningful
influence on the pharmacokinetics of saxagliptin or other drugs.
In Vivo Assessment of Drug Interactions
Effects of Saxagliptin on Other Drugs
In
studies conducted in healthy subjects, as described below, saxagliptin did
not meaningfully alter the pharmacokinetics of metformin, glyburide, pioglitazone,
digoxin, simvastatin, diltiazem, or ketoconazole.
Metformin: Coadministration
of a single dose of saxagliptin (100 mg) and metformin (1000 mg),
an hOCT-2 substrate, did not alter the pharmacokinetics of metformin in healthy
subjects. Therefore, ONGLYZA is not an inhibitor of hOCT-2-mediated transport.
Glyburide: Coadministration
of a single dose of saxagliptin (10 mg) and glyburide (5 mg), a CYP2C9 substrate,
increased the plasma Cmax of glyburide by 16%; however,
the AUC of glyburide was unchanged. Therefore, ONGLYZA does not meaningfully
inhibit CYP2C9-mediated metabolism.
Pioglitazone: Coadministration
of multiple once-daily doses of saxagliptin (10 mg) and pioglitazone (45 mg),
a CYP2C8 substrate, increased the plasma Cmax of pioglitazone
by 14%; however, the AUC of pioglitazone was unchanged.
Digoxin: Coadministration
of multiple once-daily doses of saxagliptin (10 mg) and digoxin (0.25 mg),
a P-gp substrate, did not alter the pharmacokinetics of digoxin. Therefore,
ONGLYZA is not an inhibitor or inducer of P-gp-mediated transport.
Simvastatin: Coadministration
of multiple once-daily doses of saxagliptin (10 mg) and simvastatin (40 mg),
a CYP3A4/5 substrate, did not alter the pharmacokinetics of simvastatin. Therefore,
ONGLYZA is not an inhibitor or inducer of CYP3A4/5-mediated metabolism.
Diltiazem: Coadministration
of multiple once-daily doses of saxagliptin (10 mg) and diltiazem (360 mg
long-acting formulation at steady state), a moderate inhibitor of CYP3A4/5,
increased the plasma Cmax of diltiazem by 16%; however,
the AUC of diltiazem was unchanged.
Ketoconazole: Coadministration
of a single dose of saxagliptin (100 mg) and multiple doses of ketoconazole
(200 mg every 12 hours at steady state), a strong inhibitor of CYP3A4/5 and
P-gp, decreased the plasma Cmax and AUC of ketoconazole
by 16% and 13%, respectively.
Effects of Other Drugs on Saxagliptin
Metformin: Coadministration of a single dose of saxagliptin (100 mg) and metformin
(1000 mg), an hOCT-2 substrate, decreased the Cmax of
saxagliptin by 21%; however, the AUC was unchanged.
Glyburide: Coadministration
of a single dose of saxagliptin (10 mg) and glyburide (5 mg), a CYP2C9 substrate,
increased the Cmax of saxagliptin by 8%; however, the
AUC of saxagliptin was unchanged.
Pioglitazone: Coadministration
of multiple once-daily doses of saxagliptin (10 mg) and pioglitazone (45 mg),
a CYP2C8 (major) and CYP3A4 (minor) substrate, did not alter the pharmacokinetics
of saxagliptin.
Digoxin: Coadministration
of multiple once-daily doses of saxagliptin (10 mg) and digoxin (0.25 mg),
a P-gp substrate, did not alter the pharmacokinetics of saxagliptin.
Simvastatin: Coadministration
of multiple once-daily doses of saxagliptin (10 mg) and simvastatin (40 mg),
a CYP3A4/5 substrate, increased the Cmax of saxagliptin
by 21%; however, the AUC of saxagliptin was unchanged.
Diltiazem: Coadministration
of a single dose of saxagliptin (10 mg) and diltiazem (360 mg long-acting
formulation at steady state), a moderate inhibitor of CYP3A4/5, increased
the Cmax of saxagliptin by 63% and the AUC by 2.1-fold.
This was associated with a corresponding decrease in the Cmax and
AUC of the active metabolite by 44% and 36%, respectively.
Ketoconazole: Coadministration
of a single dose of saxagliptin (100 mg) and ketoconazole (200 mg
every 12 hours at steady state), a strong inhibitor of CYP3A4/5 and P-gp,
increased the Cmax for saxagliptin by 62% and the AUC
by 2.5-fold. This was associated with a corresponding decrease in the Cmax and
AUC of the active metabolite by 95% and 91%, respectively.
In
another study, coadministration of a single dose of saxagliptin (20 mg) and
ketoconazole (200 mg every 12 hours at steady state), increased the Cmax and
AUC of saxagliptin by 2.4-fold and 3.7-fold, respectively. This was associated
with a corresponding decrease in the Cmax and AUC of
the active metabolite by 96% and 90%, respectively.
Rifampin: Coadministration
of a single dose of saxagliptin (5 mg) and rifampin (600 mg QD at steady state)
decreased the Cmax and AUC of saxagliptin by 53% and
76%, respectively, with a corresponding increase in Cmax (39%)
but no significant change in the plasma AUC of the active metabolite.
Omeprazole: Coadministration
of multiple once-daily doses of saxagliptin (10 mg) and omeprazole (40 mg),
a CYP2C19 (major) and CYP3A4 substrate, an inhibitor of CYP2C19, and an inducer
of MRP-3, did not alter the pharmacokinetics of saxagliptin.
Aluminum
hydroxide + magnesium hydroxide + simethicone: Coadministration
of a single dose of saxagliptin (10 mg) and a liquid containing aluminum hydroxide
(2400 mg), magnesium hydroxide (2400 mg), and simethicone (240 mg) decreased
the Cmax of saxagliptin by 26%; however, the AUC of
saxagliptin was unchanged.
Famotidine: Administration
of a single dose of saxagliptin (10 mg) 3 hours after a single dose of famotidine
(40 mg), an inhibitor of hOCT-1, hOCT-2, and hOCT-3, increased the Cmax of
saxagliptin by 14%; however, the AUC of saxagliptin was unchanged.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Saxagliptin did not induce tumors
in either mice (50, 250, and 600 mg/kg) or rats (25, 75, 150, and 300 mg/kg)
at the highest doses evaluated. The highest doses evaluated in mice were equivalent
to approximately 870 (males) and 1165 (females) times the human exposure at
the MRHD of 5 mg/day. In rats, exposures were approximately 355 (males) and
2217 (females) times the MRHD.
Saxagliptin was not mutagenic
or clastogenic with or without metabolic activation in an in vitro Ames
bacterial assay, an in vitro cytogenetics assay in primary
human lymphocytes, an in vivo oral micronucleus assay in
rats, an in vivo oral DNA repair study in rats, and an oral in
vivo / in vitro cytogenetics study in rat peripheral
blood lymphocytes. The active metabolite was not mutagenic in an in
vitro Ames bacterial assay.
In a rat fertility
study, males were treated with oral gavage doses for 2 weeks prior to mating,
during mating, and up to scheduled termination (approximately 4 weeks total)
and females were treated with oral gavage doses for 2 weeks prior to mating
through gestation day 7. No adverse effects on fertility were observed at
exposures of approximately 603 (males) and 776 (females) times the MRHD. Higher
doses that elicited maternal toxicity also increased fetal resorptions (approximately
2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility,
ovulation, and implantation were observed at approximately 6138 times the
MRHD.
Animal Toxicology
Saxagliptin produced adverse skin
changes in the extremities of cynomolgus monkeys (scabs and/or ulceration
of tail, digits, scrotum, and/or nose). Skin lesions were reversible at ≥20
times the MRHD but in some cases were irreversible and necrotizing at higher
exposures. Adverse skin changes were not observed at exposures similar to
(1 to 3 times) the MRHD of 5 mg. Clinical correlates to skin lesions in monkeys
have not been observed in human clinical trials of saxagliptin.
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