adult sub populations as assessed by less than twofold differences in the sum of
Saxagliptin and active metabolite exposures including by age, gender, weight, hepatic
impairment or mild renal impairment. Higher Saxagliptin and active metabolite
exposures were noted in patients with moderate or severe renal impairment and end stage
renal disease. These patients will be managed with a dose adjustment to one half of the
usual clinical dose, that is, to 2.5 mgs once daily.
In the clinical pharmacology program Saxagliptin given once daily was
generally safe and well tolerated at doses up to 400 mgs for two weeks. That is 80x the
pharmacokinetic drug-drug interactions with a number of commonly used oral
antidiabetic agents as well as other agents commonly used in this patient population
including a Statin, gastric acid controllers, and Digoxin. Drug-drug interactions with
strong CYP3A inhibitors or induces are minimized because changes in parent drug
exposures were offset by opposite changes in active metabolite exposures.
In a series of drug-drug interaction studies we found low potential for
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of a wide range of Saxagliptin doses from 1 to 400 mgs once daily. This enabled
robust conclusions regarding dose selection as well as safety experience at doses in great
excess of our proposed usual clinical dose. The program included over 670 subjects in
clinical pharmacology studies, 423 patients in a phase 2b dose ranging study and over
4,200 patients with type 2 diabetes in phase 3 clinical trials.
proposed usual clinical dose of 5 mgs. There were no signals for QT prolongation or
heart rate changes seen in a thorough QTC study. We observed no safety signals for
hypoglycemia, localized edema or skin lesions. In addition, we saw no hepatics, striated
muscle, and renal safety signals in laboratory blood tests.
We observed no clinically meaningful pharmacokinetic differences in