formin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate to changes in glycemic control in patients with type 2 diabetes.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.
Cardiac Electrophysiology
In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline was observed at 3 hours postdose and was 8.0 msec. This increase is not considered to be clinically significant. At the 800 mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100 mg dose.
In patients with type 2 diabetes administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
Simvastatin
Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
12.3 Pharmacokinetics
General
JUVISYNC
The results of bioequivalence studies in healthy subjects demonstrated that JUVISYNC (sitagliptin and simvastatin) is bioequivalent to coadministration of sitagliptin and simvastatin as individual tablets.
Sitagliptin and simvastatin do not have a clinically meaningful pharmacokinetic interaction.
Absorption
JUVISYNC
A high-fat breakfast did not affect sitagliptin exposure following administration of JUVISYNC, while simvastatin AUC decreased by 24%, simvastatin Cmax increased by 20%, and simvastatin acid AUC and Cmax increased by 37% and 116%, respectively. The clinical significance of the above exposure changes in simvastatin and simvastatin acid is not known. JUVISYNC is recommended to be taken in the evening as indicated in simvastatin labeling.
Sitagliptin
The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 µM∙hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.
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