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Pharmacology: Pharmacodynamics: Sitagliptin phosphate: General: In patients with type 2 diabetes, administration of single oral doses of sitagliptin leads to inhibition of DPP-4 enzyme activity for a 24-hour period, resulting in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, increased plasma levels of insulin and C-peptide, decreased glucagon concentrations, reduced fasting glucose, and reduced glucose excursion following an oral glucose load or a meal.
In Phase III clinical studies of 18- and 24-week duration, treatment with sitagliptin 100 mg daily in patients with type 2 diabetes significantly improved beta cell function, as assessed by several markers, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In Phase II studies, sitagliptin 50 mg twice daily provided similar glycemic efficacy compared to sitagliptin 100 mg once daily.
In a randomized, placebo-controlled, double-blind, double-dummy, four-period crossover two-day study in healthy adult subjects, the effects on post-meal plasma concentrations of active and total GLP-1 and glucose after co-administration of sitagliptin and metformin were compared with those after administration of sitagliptin alone, metformin alone or placebo, each administered for two days. The incremental 4-hour post-meal weighted mean active GLP-1 concentrations were increased approximately 2-fold after either administration of sitagliptin alone or metformin alone compared with placebo. The effect on active GLP-1 concentrations after co-administration of sitagliptin and metformin were additive, with active GLP-1 concentrations increased by approximately 4-fold compared with placebo. Sitagliptin alone increased only active GLP-1 concentrations, reflecting inhibition of DPP-4, whereas metformin alone increased active and total GLP-1 concentrations to a similar extent. These data are consistent with different mechanisms for the increase in active GLP-1 concentrations. Results from the study also demonstrated that sitagliptin, but not metformin, enhances active GIP concentrations.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia, suggesting that the insulinotropic and glucagon suppressive actions of the drug are glucose dependent.
Effects on blood pressure: In a randomized, placebo-controlled crossover study in hypertensive patients on one or more anti-hypertensive drugs (including angiotensin-converting enzyme inhibitors, angiotensin-II antagonists, calcium-channel blockers, beta-blockers and diuretics), co-administration with sitagliptin was generally well tolerated. In these patients, sitagliptin had a modest blood pressure lowering effect; 100 mg per day of sitagliptin reduced 24-hour mean ambulatory systolic blood pressure by approximately 2 mmHg, as compared to placebo. Reductions have not been observed in subjects with normal blood pressure.
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 at 3 hours postdose was 8.0 msec. This small increase was 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.
Pharmacokinetics: SITAGLIPTIN + METFORMIN HCl (JANUMET): The results of a definitive bioequivalence study in healthy subjects demonstrated that the SITAGLIPTIN + METFORMIN HCl (JANUMET) 50 mg/500 mg and 50 mg/1 g combination tablets are bioequivalent to co-administration of corresponding doses of SITAGLIPTIN PHOSPHATE (JANUVIA) and metformin hydrochloride as individual tablets.
Because bioequivalence is demonstrated at the lowest and highest combination tablet dose strengths available, bioequivalence is conferred to the (sitagliptin/metformin) 50 mg/850 mg fixed dose combination (FDC) tablet.
Absorption: Sitagliptin phosphate: The absolute bioavailability of sitagliptin is approximately 87%. Co-administration of a high-fat meal with sitagliptin phosphate had no effect on the pharmacokinetics of sitagliptin.
Metformin hydrochloride: The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alternation in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution: Sitagliptin phosphate: The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metformin hydrochloride: The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism: Sitagliptin phosphate: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.
Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Metformin hydrochloride: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.
Elimination: Sitagliptin phosphate: Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t½ following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
Metformin hydrochloride: Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Characteristics in Patients: Type 2 Diabetes: Sitagliptin phosphate: The pharmacokinetics of sitagliptin in patients with type 2 diabetes are generally similar to those in healthy subjects.
Metformin hydrochloride: In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects, nor is there any accumulation of metformin in either group at usual clinical doses.
Renal Impairment: SITAGLIPTIN + METFORMIN HCl (JANUMET): SITAGLIPTIN + METFORMIN HCl (JANUMET) should not be used in patients with renal impairment (see Contraindications).
Sitagliptin phosphate: An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal insufficiency, and an approximately 4-fold increase was observed in patients with severe renal insufficiency and in patients with ESRD on hemodialysis, as compared to normal healthy control subjects.
Metformin hydrochloride: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Hepatic Impairment: Sitagliptin phosphate: In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100 mg dose of sitagliptin phosphate. These differences are not considered to be clinically meaningful.
There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9). However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Gender: Sitagliptin phosphate: Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Elderly: Sitagliptin phosphate: Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Metformin hydrochloride: Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Glucophage prescribing information: Pharmacology: Special Populations: Geriatrics under Actions).
Pediatric: The pharmacokinetics of sitagliptin (single dose of 50 mg, 100 mg or 200 mg) were investigated in pediatric patients (10 to 17 years of age) with type 2 diabetes. In this population, the dose-adjusted AUC of sitagliptin in plasma was approximately 18% lower compared to adult patients with type 2 diabetes for a 100 mg dose. This is not considered to be a clinically meaningful difference based on the flat PK/PD relationship between the dose of 50 mg and 100 mg in adults.
No studies with sitagliptin have been performed in pediatric patients < 10 years of age.
Race: Sitagliptin phosphate: Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data, including subjects of White, Hispanic, Black, Asian, and other racial groups.
Metformin hydrochloride: No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).
Body Mass Index (BMI): Sitagliptin phosphate: Body mass index (BMI) had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
