Pharmacology: Pharmacodynamics: Sitagliptin: General:
In patients with type 2 diabetes, administration of sitagliptin led to inhibition of dipeptidyl peptidase-4 (DPP-4) enzyme activity for a 24-hr period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
Sitagliptin and Metformin HCl Co-Administration:
In a 2-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear what these findings mean for changes in glycemic control in patients with type 2 diabetes.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.
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 hrs post-dose was 8 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.
Mechanism of Action:
Janumet combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: Sitagliptin phosphate, a DPP-4 inhibitor and metformin HCl, a member of the biguanide class.
Sitagliptin phosphate is a DPP-4 inhibitor which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including GLP-1 and GIP, are released by the intestine throughout the day and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic β-cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic α-cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro
at concentrations approximating those from therapeutic doses.
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects [except in special circumstances (see Precautions)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
The co-administration of sitagliptin and metformin has been studied in patients with type 2 diabetes inadequately controlled on diet and exercise and in combination with other antihyperglycemic agents.
There have been no clinical efficacy studies conducted with Janumet; however, bioequivalence of Janumet with co-administered sitagliptin and metformin HCl tablets was demonstrated.
Sitagliptin and Metformin Co-Administration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise:
A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin and metformin co-administration. Patients on an antihyperglycemic agent (n=541) underwent a diet, exercise and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5-11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (n=550) with inadequate glycemic control (A1C 7.5-11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive placebo, sitagliptin 100 mg once daily, metformin 500 mg or 1000 mg twice daily, or sitagliptin 50 mg twice daily in combination with metformin 500 mg or 1000 mg twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.
Sitagliptin and metformin co-administration provided significant improvements in A1C, FPG and 2-hr PPG compared to placebo, to metformin alone, and to sitagliptin alone (Table 1 and Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: Sitagliptin 100 mg once daily, -1.1%; metformin 500 mg twice daily, -1.1%; metformin 1000 mg twice daily, -1.2%; sitagliptin 50 mg twice daily with metformin 500 mg twice daily, -1.6%; sitagliptin 50 mg twice daily with metformin 1000 mg twice daily, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo. (See Table 1 and Figure 1.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In addition, this study included patients (n=117) with more severe hyperglycemia (A1C >11% or blood glucose >280 mg/dL) who were treated with twice daily open-label sitagliptin 50 mg and metformin 1000 mg. In this group of patients, the mean baseline A1C value was 11.2%, mean FPG was 314 mg/dL, and mean 2-hr PPG was 441 mg/dL. After 24 weeks, mean decreases from baseline of -2.9% for A1C, -127 mg/dL for FPG, and -208 mg/dL for 2-hr PPG were observed.
Initial combination therapy or maintenance of combination therapy should be individualized and are left to the discretion of the healthcare provider.
Sitagliptin Add-On Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone:
A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin. Patients already on metformin (N=431) at a dose of at least 1500 mg/day were randomized after completing a 2-week, single-blind placebo run-in period. Patients on metformin and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin (at a dose of at least 1500 mg/day) in monotherapy. Patients were randomized to the addition of either sitagliptin 100 mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.
In combination with metformin , sitagliptin provided significant improvements in A1C, FPG and 2-hr PPG compared to placebo with metformin (Table 2). Rescue glycemic therapy was used in 5% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups. (See Table 2.)
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Sitagliptin Add-On Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin and Glimepiride:
A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with glimepiride, with or without metformin. Patients entered a run-in treatment period on glimepiride (≥4 mg/day) alone or glimepiride in combination with metformin (≥1500 mg/day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5-10.5%) were randomized to the addition of either sitagliptin 100 mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.
Patients receiving sitagliptin with metformin and glimepiride had significant improvements in A1C and FPG compared to patients receiving placebo with metformin and glimepiride, with mean reductions from baseline relative to placebo in A1C of -0.9% and in FPG of -21 mg/dL. Rescue therapy was used in 8% of patients treated with add-on sitagliptin 100 mg and 29% of patients treated with add-on placebo. The patients treated with add-on sitagliptin had a mean increase in body weight of 1.1 kg versus add-on placebo (+0.4 kg vs -0.7 kg). In addition, add-on sitagliptin resulted in an increased rate of hypoglycemia compared to add-on placebo (see Precautions and Adverse Reactions). (See Table 3.)
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Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin and Insulin:
A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin as add-on to insulin therapy. Approximately 75% of patients were also taking metformin. Patients entered a 2-week, single-blind, run-in treatment period on premixed, long-acting, or intermediate-acting insulin, with or without metformin (≥1500 mg/day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a premixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5-11%) were randomized to the addition of either sitagliptin 100 mg (N=229) or placebo (N=233), administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.
Among patients also receiving metformin, the median daily insulin (premixed, intermediate or long-acting) dose at baseline was 40 units in the sitagliptin-treated patients and 42 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was 0 for both groups at the end of the study. Patients receiving sitagliptin with metformin and insulin had significant improvements in A1C, FPG and 2-hr PPG compared to patients receiving placebo with metformin and insulin. The adjusted mean change from baseline in body weight was -0.3 kg in patients receiving sitagliptin with metformin and insulin and -0.2 kg in patients receiving placebo with metformin and insulin. There was an increased rate of hypoglycemia in patients treated with sitagliptin (see Precautions and Adverse Reactions). (See Table 4.)
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Sitagliptin Add-On Therapy Versus Glipizide Add-On Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin:
The efficacy of sitagliptin was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin monotherapy (dose of ≥1500 mg/day) which included washout of medications other than metformin, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5-10%) were randomized 1:1 to the addition of sitagliptin 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.
After 52 weeks, sitagliptin and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 5). These results were consistent with the per protocol analysis (see Figure 2). A conclusion in favor of the noninferiority of sitagliptin to glipizide may be limited to patients with baseline A1C comparable to those included in the study (>70% of patients had baseline A1C <8% and >90% had A1C <9%). (See Table 5 and Figure 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32%). Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs +1.1 kg).
The results of a bioequivalence study in healthy subjects demonstrated that the Janumet (sitagliptin phosphate/metformin HCl) 50 mg/500 mg and 50 mg/1000 mg combination tablets are bioequivalent to co-administration of corresponding doses of sitagliptin (Januvia) and metformin HCl 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.
The absolute bioavailability of sitagliptin phosphate is approximately 87%. Co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin.
The absolute bioavailability of a metformin HCl 500-mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin HCl tablets 500-1500 mg and 850-2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration 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-min 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.
The mean volume of distribution at steady state following a single 100-mg IV dose of sitagliptin to healthy subjects is approximately 198 L. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are >90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin HCl tablets, steady-state plasma concentrations of metformin are reached within 24-48 hrs 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.
Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
Following a [14
C] sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six (6) 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.
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.
Following administration of an oral [14
C] sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within 1 week of dosing. The apparent terminal t½
following a 100-mg oral dose of sitagliptin was approximately 12.4 hrs 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, cyclosporin, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
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 hrs, with a plasma elimination t½
of approximately 6.2 hrs. In blood, the elimination t½
is approximately 17.6 hrs, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations: Renal Insufficiency:
Janumet should not be used in patients with renal insufficiency (see Contraindications and Precautions).
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, including patients with ESRD on hemodialysis, as compared to normal healthy control subjects.
In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood t½
of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Hepatic Insufficiency: Sitagliptin:
In patients with moderate hepatic insufficiency (Child-Pugh score 7-9), 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. These differences are not considered to be clinically meaningful.
There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.
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 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.
When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65-80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the t½
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).
Janumet treatment should not be initiated in patients ≥80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced (see Precautions).
No studies with Janumet have been performed in pediatric patients.
Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of White, Hispanic, Black, Asian and other racial groups.
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:
Body mass index 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.
Drug Interactions: Sitagliptin and Metformin HCl:
Co-administration of multiple doses of sitagliptin 50 mg and metformin 1000 mg given twice daily did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes.
Pharmacokinetic drug interaction studies with Janumet have not been performed, however, such studies have been conducted with the individual components of Janumet (sitagliptin and metformin HCl).
Sitagliptin: In Vitro Assessment of Drug Interactions:
Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6 and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein-binding displacement is very low.
In Vivo Assessment of Drug Interactions: Effect of Sitagliptin on Other Drugs:
In clinical studies, as described on the following text, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin or oral contraceptives, providing in vivo
evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9 and organic cationic transporter (OCT).
Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of digoxin 0.25 mg concomitantly with sitagliptin 100 mg daily for 10 days, the plasma AUC of digoxin was increased by 11% and the plasma Cmax
Single dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (eg, glipizide, tolbutamide and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9 (see Precautions).
Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.
Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that sitagliptin is not an inhibitor of CYP2C8-mediated metabolism.
Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers or pharmacodynamics [as assessed by measurement of prothrombin International Normalized Ratio (INR)] of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.
Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
Effect of Other Drugs on Sitagliptin:
Clinical data described as follows suggest that sitagliptin is not susceptible to clinically meaningfully interactions by co-administered medications.
A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100-mg oral dose of sitagliptin and a single 600-mg oral dose of cyclosporine increased the AUC and Cmax
of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Toxicology: Carcinogenicity, Mutagenicity & Impairment of Fertility:
No animal studies have been conducted with the combined products in Janumet to evaluate carcinogenesis, mutagenesis or impairment of fertility. The following data are based on the findings in studies with sitagliptin and metformin individually.
A 2-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin 50, 150 and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A 2-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin 50, 125, 250 and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro
cytogenetics assay in CHO, an in vitro
rat hepatocyte DNA alkaline elution assay and an in vivo
In rat fertility studies with oral gavage doses of 125, 250 and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparisons).
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of a mutagenic potential of metformin in the following in vitro
tests: Ames test (S. typhimurium
), gene mutation test (mouse lymphoma cells) or chromosomal aberrations test (human lymphocytes). Results in the in vivo
mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.