New Drug Update 2009-2010 - LAFP

SAXAGLIPTIN - Onglyza (Bristol-Myers Squibb / Astra Zeneca) 1S
INDICATIONS: Saxagliptin is indicated for use as an adjunct to diet and exercise to improve glycemic
control in adults with type 2 diabetes mellitus. It has been evaluated for use as monotherapy or in
combination with other antidiabetic agents, including metformin, sulfonylureas, and thiazolidinediones. It
has not been assessed in combination with insulin.
Saxagliptin and sitagliptin share the same Food and Drug Administration (FDA)-approved indication.
CLINICAL PHARMACOLOGY: Saxagliptin is a reversible, competitive dipeptidyl peptidase-4 (DPP-4)
inhibitor. DPP-4 inhibitors lower blood glucose by preventing the breakdown of glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus prolonging the activity of these
peptides. Saxagliptin is 10-fold more potent than sitagliptin and vildagliptin at inhibiting DPP-4. The
saxagliptin active metabolite is 2-fold less potent than saxagliptin. Both saxagliptin and its active
metabolite are more selective for inhibition of DPP-4 than DPP-8 (400- and 950-fold) and DPP-9 (75- and
160-fold). Saxagliptin and its active metabolite have exhibited slow dissociation from DPP-4, with a halflife
of dissociation of 50 and 23 minutes, respectively. Plasma DPP-4 inhibition 24 hours after saxagliptin
2.5 and 400 mg doses was 50% and 79% of predose, respectively. Maximal inhibition was observed at a
150 mg dose.
After an oral glucose load or meal, saxagliptin DPP-4 inhibition results in a 2- to 3-fold increase in
circulating levels of active GLP-1 and GIP, decreased glucagon concentration, and increased insulin
secretion from pancreatic beta-cells.
PHARMACOKINETICS: Saxagliptin has high oral bioavailability (75% in animal models). Systemic
exposure is dose-proportional over doses from 2.5 to 400 mg. Peak concentrations (C max ) of saxagliptin
are reached within 2 hours of oral administration; C max of the active metabolite are reached within 4 hours.
Administration with a high-fat meal slightly delayed absorption (approximately 20 minutes), but was
associated with a 27% increase in overall exposure.
Saxagliptin is metabolized via CYP 3A4/5. Mean saxagliptin half-life is 2.2 to 3.8 hours; the half-life of the
active metabolite is 3 to 7.4 hours. 6 Approximately 70% of the dose is recovered in the urine as
saxagliptin or the active metabolite; 12% to 29% was recovered as the parent drug.
Saxagliptin pharmacokinetics did not differ by gender, although levels of the active metabolite were
increased approximately 25% in females.
Saxagliptin C max were increased 1.2-fold and area under the curve (AUC) values were increased 1.6-fold
in elderly subjects compared with younger subjects. Elderly subjects had a greater volume of distribution
and reduced metabolic and renal clearance of saxagliptin. Age-related decline in renal function accounted
for 50% of the difference in pharmacokinetics. Dosage adjustments on the basis of age are not
necessary.
In patients with hepatic function impairment (Child-Pugh class A, B, or C), a trend toward increased
saxagliptin levels (AUC increased 10% to 77%) and reduced levels of the active metabolite (AUC reduced
by 7% to 33%) were observed; however, routine dosage adjustments do not appear necessary.
In patients with mild renal impairment, the AUC of saxagliptin and its active metabolite were 20% and
70%, higher, respectively, than those in patients with healthy renal function. In patients with moderate to
severe renal impairment, AUC levels of saxagliptin and its active metabolite were up to 2.1- and 4.5-fold
higher than in patients with healthy renal function. Dose restrictions are advised for patients with
moderate and severe renal impairment and patients with end-stage renal disease requiring hemodialysis.
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