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Pharmacology: Mechanism of Action: JANUVIA is a member of a class of oral anti-hyperglycemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors, which improve glycemic control in patients with type 2 diabetes by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. 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 beta cells by intracellular signaling pathways involving cyclic AMP. Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycemia, these changes in insulin and glucagon levels lead to lower hemoglobin A1c (HbA1c) and lower fasting and post-prandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulfonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycemia in patients with type 2 diabetes and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.
Pharmacodynamics: General: In patients with type 2 diabetes, administration of single oral doses of JANUVIA 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 a study of patients with type 2 diabetes inadequately controlled on metformin monotherapy, glucose levels monitored throughout the day were significantly lower in patients who received sitagliptin 100 mg per day (50 mg twice daily) in combination with metformin compared with patients who received placebo with metformin (see Figure 1).
Click on icon to see table/diagram/imageIn Phase III clinical studies of 18- and 24-week duration, treatment with JANUVIA 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, JANUVIA 50 mg twice daily provided no additional glycemic efficacy compared to 100 mg once daily.
In a randomized, placebo-controlled, double-blind, double-dummy, four-period crossover 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 by 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, JANUVIA 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 JANUVIA was generally well tolerated. In these patients, JANUVIA had a modest blood pressure lowering effect; 100 mg per day of JANUVIA 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 JANUVIA 100 mg, JANUVIA 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 JANUVIA 100 mg (N=81) or JANUVIA 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.
Clinical Studies: There were approximately 5200 patients with type 2 diabetes randomized in nine double-blind, placebo-controlled Phase III clinical studies conducted to evaluate the effects of sitagliptin on glycemic control. Co-morbid diseases, including dyslipidemia and hypertension, were common in the patients studied and more than 50% were obese (BMI ≥30 kg/m2). The majority of patients met National Cholesterol Education Program (NCEP) criteria for metabolic syndrome. These studies included white, Hispanic, black, Asian, and other racial and ethnic groups, and patients had an overall mean age of approximately 55 years.
Additional double-blind, placebo-controlled clinical studies were conducted, one in 151 Japanese patients with type 2 diabetes and another in 91 patients with type 2 diabetes and moderate to severe renal insufficiency.
An active (glipizide)-controlled study of 52-weeks duration was conducted in 1172 patients with type 2 diabetes who had inadequate glycemic control on metformin.
In patients with type 2 diabetes, treatment with JANUVIA produced clinically significant improvements in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) and 2-hour postprandial glucose (PPG) compared to placebo. In the active (glipizide)-controlled study, clinically significant improvements in glycemic control were maintained for 52 weeks. JANUVIA provided improvement in measures of beta cell function (see Pharmacology: Pharmacodynamics under Actions).
Clinical Studies Monotherapy: A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of JANUVIA monotherapy. Patients with inadequate glycemic control (HbA1c 7% to 10%) were randomized to receive a 100-mg or 200-mg dose of JANUVIA or placebo once daily.
Treatment with JANUVIA at 100 mg daily provided significant improvements in HbA1c, FPG, and 2-hour PPG compared to placebo (Tables 1 and 2). These studies included patients with a wide range of baseline HbA1c. The improvement in HbA1c compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, baseline BMI, presence of metabolic syndrome, or a standard index of insulin resistance (HOMA-IR). Patients with a shorter length of time since diagnosis of diabetes (<3 years) or with higher baseline HbA1c had greater reductions in HbA1c. In the 18- and 24-week studies, among patients who were not on an antihyperglycemic agent at study entry, the reduction from baseline in HbA1c was -0.67% and -0.85%, respectively, for those given JANUVIA and -0.10% and -0.18%, respectively, for those given placebo. In both studies, JANUVIA provided a significant reduction compared with placebo in FPG (-19.3 mg/dL in the 18-week study and -15.8 mg/dL in the 24-week study) at 3 weeks, the first time point at which FPG was measured. Overall, the 200-mg daily dose did not provide greater glycemic efficacy than the 100-mg daily dose. The effect of JANUVIA on lipid endpoints was similar to placebo. Body weight did not increase from baseline with JANUVIA therapy in either study, compared to a small reduction in patients given placebo (Table 2). The observed incidence of hypoglycemia in patients treated with JANUVIA was similar to placebo. (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageAdditional Monotherapy Studies: A double-blind, placebo-controlled study in Japanese patients with type 2 diabetes was performed to examine the efficacy of treatment with JANUVIA 100 mg once daily compared to placebo. This study included 151 patients (75 treated with JANUVIA, 76 treated with placebo) with mean age of 55.3 years, baseline BMI of 25.2 kg/m2, mean baseline HbA1C of 7.6%, and mean baseline FPG of 163 mg/dL. After 12 weeks, JANUVIA provided a 1.05% decrease in HbA1C relative to placebo (JANUVIA -0.65% change from baseline, placebo 0.41%, p<0.001). FPG decreased by 31.9 mg/dL relative to placebo (JANUVIA -22.5 mg/dL change from baseline, placebo 9.4 mg/dL, p<0.001).
A multinational, randomized, double-blind, placebo-controlled study was also conducted to assess the safety and tolerability of JANUVIA in 91 patients with type 2 diabetes and chronic renal insufficiency (creatinine clearance <50 mL/min). Patients with moderate renal insufficiency received 50 mg daily of JANUVIA and those with severe renal insufficiency or with ESRD on hemodialysis or peritoneal dialysis received 25 mg daily. In this study, the safety and tolerability of JANUVIA were generally similar to placebo. In addition, the reductions in HbA1C and FPG with JANUVIA compared to placebo were generally similar to those observed in other monotherapy studies. (See Pharmacology: Pharmacokinetics: Characteristics in Patients, Renal Impairment.)
Initial Combination Therapy with Metformin: 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 safety and efficacy of initial therapy with the combination of sitagliptin and metformin. Approximately equal numbers of patients were randomized to receive initial therapy with placebo, 100 mg of sitagliptin (JANUVIA) once daily, 500 mg or 1000 mg of metformin twice daily or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily.
Initial therapy with the combination of sitagliptin and metformin provided significant improvements in HbA1c, FPG and 2-hour PPG compared to placebo, to metformin alone and to sitagliptin alone (p<0.001; Table 3). An improvement in FPG, with near maximal FPG reduction, was achieved by the 3-week time point (the first point assessed after initiation of therapy) and sustained throughout the 24-week study. Measures of beta cell function, HOMA-β and the proinsulin to insulin ratio, also showed greater improvement with the co-administration of sitagliptin and metformin compared with either monotherapy alone. 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. Mean reductions from baseline in HbA1c compared with placebo were generally greater for patients with higher baseline HbA1c values. The improvement in HbA1c was generally consistent across subgroups defined by gender, age, race, or baseline BMI. Mean reductions from baseline in HbA1c for patients not on an antihyperglycemic agent at study entry were: JANUVIA 100 mg once daily, -1.06%; metformin 500 mg bid, -1.09%; metformin 1000 mg bid, -1.24%; sitagliptin 50 mg bid with metformin 500 mg bid, -1.59%; and sitagliptin 50 mg bid with metformin 1000 mg bid, -1.94%; and for patients receiving placebo, -0.17%. (See Table 3.)
Click on icon to see table/diagram/imageIn addition, this study included patients (N=117) with more severe hyperglycemia (HbA1c >11% or blood glucose >280 mg/dL) who were treated with open-label sitagliptin at 50 mg and metformin at 1000 mg twice daily. In this group of patients, the baseline HbA1c value was 11.15%, FPG was 314.4 mg/dL, and 2-hour PPG was 441.0 mg/dL. After 24 weeks, decreases from baseline of -2.94% for HbA1c, -126.7 mg/dL for FPG, and -207.9 mg/dL for 2-hour PPG were observed. In this open-label cohort, a modest increase in body weight of 1.3 kg was observed at 24 weeks.
Add-on Combination Therapy with Metformin: 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 JANUVIA in combination with metformin. All patients were started on metformin monotherapy and the dose increased to at least 1500 mg per day. Patients were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily.
In combination with metformin, JANUVIA provided significant improvements in HbA1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 4). The improvement in HbA1C compared to placebo was not affected by baseline HbA1C, prior antihyperglycemic therapy, gender, age, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, or standard indices of insulin resistance (HOMA-IR) or insulin secretion (HOMA-β). Compared to patients taking placebo, patients taking JANUVIA demonstrated slight decreases in total cholesterol, non-HDL cholesterol and triglycerides. A similar decrease in body weight was observed for both treatment groups. (See Table 4.)
Click on icon to see table/diagram/imageActive-Controlled Study with Glipizide: Long-term maintenance of effect was evaluated in a 52-week, double-blind, glipizide-controlled trial in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy at ≥1500 mg/day. In this study, patients were randomized to the addition of either JANUVIA 100 mg daily (N=588) or glipizide (N=584) for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated by the investigator to a target FPG of <110 mg/dL, without significant hypoglycemia, over the next 18 weeks. A maximum dosage of 20 mg/day was allowed to optimize glycemic control. Thereafter, the glipizide dose was to have been kept constant. The mean dose of glipizide after the titration period was 10.3 mg.
Both treatments resulted in a statistically significant improvement in glycemic control from baseline. After 52 weeks, the reduction from baseline in HbA1c was 0.67% for JANUVIA 100 mg daily and 0.67% for glipizide, confirming comparable efficacy of the two agents. The reduction in FPG was 10.0 mg/dL for JANUVIA and 7.5 mg/dL for glipizide. In a post-hoc analysis, patients with higher baseline HbA1c (≥9%) in both groups had greater reductions from baseline in HbA1c (JANUVIA, -1.68%; glipizide, -1.76%). In this study, the proinsulin to insulin ratio, a marker of efficiency of insulin synthesis and release, improved with JANUVIA and deteriorated with glipizide treatment. The incidence of hypoglycemia in the JANUVIA group (4.9%) was significantly lower than that in the glipizide group (32.0%). Patients treated with JANUVIA 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).
Add-on Combination Therapy with Pioglitazone: A total of 353 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with pioglitazone. All patients were started on pioglitazone monotherapy at a dose of 30-45 mg per day. Patients were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Glycemic endpoints measured included HbA1c and fasting glucose.
In combination with pioglitazone, JANUVIA provided significant improvements in HbA1c and FPG compared to placebo with pioglitazone (Table 5). The improvement in HbA1c compared to placebo was not affected by baseline HbA1c, prior antihyperglycemic therapy, gender, age, race, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, or standard indices of insulin resistance (HOMA-IR) or insulin secretion (HOMA-β). Compared to patients taking placebo, patients taking JANUVIA demonstrated a slight decrease in triglycerides. There was no significant difference between JANUVIA and placebo in body weight change. (See Table 5.)
Click on icon to see table/diagram/imageAdd-on Combination Therapy with Glimepiride or Glimepiride plus Metformin: 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 JANUVIA in combination with glimepiride (≥4 mg per day) or glimepiride with metformin (≥1500 mg per day). Patients were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Glycemic endpoints measured included HbA1c and fasting glucose.
In combination with glimepiride or glimepiride plus metformin, JANUVIA provided significant improvements in HbA1c and FPG compared to placebo (Table 6). In the entire study population (both patients on glimepiride and patients on glimepiride with metformin), a reduction from baseline relative to placebo in HbA1c of -0.74% and in FPG of -20.1 mg/dL was seen. The improvement in HbA1c compared to placebo was generally consistent across subgroups defined by gender, age, race, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, or standard indices of insulin resistance (HOMA-IR) or insulin secretion (HOMA-β). Patients treated with JANUVIA had a modest increase in body weight compared to those given placebo. (See Table 6.)
Click on icon to see table/diagram/imageAdd-on Combination Therapy with Metformin plus Rosiglitazone: A total of 262 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of JANUVIA in combination with metformin and rosiglitazone. Patients with inadequate glycemic control on a stable regimen of metformin (≥1500 mg per day) and rosiglitazone (≥4 mg per day) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Glycemic parameters were evaluated at the primary time point of Week 18 and at Week 54.
In combination with metformin and rosiglitazone, JANUVIA provided significant improvements in HbA1c, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 7, Figure 2) at Week 18, with improvements sustained through the end of the study. Lipid effects were generally neutral. There was no significant difference between JANUVIA and placebo in body weight change. (See Table 7 and Figure 2.)
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Click on icon to see table/diagram/imageAdd-on Combination Therapy with Insulin (with or without Metformin): 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 JANUVIA as add-on combination therapy with a stable dose of insulin (with or without metformin). Patients on pre-mixed, long-acting, or intermediate-acting insulin with or without metformin (≥1500 mg per day) were randomized to the addition of either 100 mg of JANUVIA or placebo, administered once daily. Glycemic endpoints measured included HbA1c, fasting glucose, and 2-hour post-prandial glucose.
In combination with insulin (with or without metformin), JANUVIA provided significant improvements in HbA1c, FPG, and 2-hour PPG compared to placebo (Table 8). The improvement in HbA1c compared to placebo was generally consistent across subgroups defined by gender, age, race, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, and standard indices of insulin resistance (HOMA-IR) and insulin secretion (HOMA-β). There was no significant difference between JANUVIA and placebo in body weight change. (See Table 8.)
Click on icon to see table/diagram/imageIn another 24-week, randomized, double-blind, placebo-controlled study designed to assess the insulin-sparing efficacy of JANUVIA as add-on combination therapy, 660 patients with inadequate glycemic control on insulin glargine with or without metformin (≥1500 mg per day) were randomized to the addition of either 100 mg of JANUVIA (N=330) or placebo (N=330), administered once daily while undergoing intensification of insulin therapy. Baseline HbA1c was 8.74% and baseline insulin dose was 37 IU/day. Patients were instructed to titrate their insulin glargine dose based on fingerstick fasting glucose values. Glycemic endpoints measured included HbA1c and FPG.
At Week 24, the increase in daily insulin dose was 20% smaller in patients treated with JANUVIA (19 IU/day) than in patients treated with placebo (24 IU/day). The difference in insulin dose (-5 IU/day) was statistically significant (p=0.009). The reduction in HbA1c in patients treated with JANUVIA and insulin (with or without metformin) was -1.31% compared to -0.87% in patients treated with placebo and insulin (with or without metformin), a difference of -0.45% [95% CI: - 0.60, -0.29]. The reduction in FPG in patients treated with JANUVIA and insulin (with or without metformin) was -55.5 mg/dL compared to -44.8 mg/dL in patients treated with placebo and insulin (with or without metformin), a difference of -10.7 mg/dL [95% CI: -17.2, - 4.3]. The incidence of hypoglycemia was 25.2% in patients treated with JANUVIA and insulin (with or without metformin) and 36.8% in patients treated with placebo and insulin (with or without metformin). The difference in incidence of hypoglycemia (-11.6%) was statistically significant (p=0.001).
TECOS Cardiovascular Safety Study: The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was a randomized study in 14,671 patients in the intention-to-treat population with an HbA1C of ≥6.5 to 8.0% with established CV disease who received JANUVIA (7,332) 100 mg daily (or 50 mg daily if the baseline eGFR was ≥30 and <50 mL/min/1.73 m2) or placebo (7,339) added to usual care targeting regional standards for HbA1C and CV risk factors. Patients with an eGFR <30 mL/min/1.73 m2 were not to be enrolled in the study. The study population included 2,004 patients ≥75 years of age and 3,324 patients with renal impairment (eGFR <60 mL/min/1.73 m2).
Over the course of the study, the overall estimated mean (SD) difference in HbA1C between the sitagliptin and placebo groups was 0.29% (0.01), 95% CI (-0.32, -0.27); p<0.001. Patients in the sitagliptin group received fewer antihyperglycemic agents than did those in the placebo group (hazard ratio 0.72; 95% CI, 0.68 to 0.77; p≤0.001) and, among patients not on insulin at study entry, were less likely to start chronic insulin therapy (hazard ratio 0.70; 95% CI, 0.63 to 0.79; p<0.001).
The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina. Secondary cardiovascular endpoints included the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke; first occurrence of the individual components of the primary composite; all-cause mortality; and hospital admissions for congestive heart failure.
After a median follow up of 3 years, JANUVIA, when added to usual care, did not increase the risk of major adverse cardiovascular events or the risk of hospitalization for heart failure compared to usual care without JANUVIA in patients with type 2 diabetes (see Table 9).
Click on icon to see table/diagram/imageJANUVIA in Pediatric Patients with Type 2 Diabetes and Inadequate Glycemic Control: A 54-week, double-blind study was conducted to evaluate the efficacy and safety of JANUVIA 100 mg once daily in pediatric patients (10 to 17 years of age) with type 2 diabetes who were not on anti-hyperglycaemic therapy for at least 12 weeks (with HbA1c 6.5% to 10%) or were on a stable dose of insulin for at least 12 weeks (with HbA1c 7% to 10%). Patients were randomized to JANUVIA 100 mg or placebo once daily for 20 weeks.
Mean baseline HbA1c was 7.5%. Treatment with JANUVIA 100 mg did not provide significant improvement in HbA1c at 20 weeks. The reduction in HbA1c in patients treated with JANUVIA (N=95) was 0.0% compared to 0.2% in patients treated with placebo (N=95), a difference of -0.2% (95% CI: -0.7, 0.3).
Pharmacokinetics: The pharmacokinetics of sitagliptin have 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 post-dose. 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 were generally similar in healthy subjects and in patients with type 2 diabetes.
Absorption: The absolute bioavailability of sitagliptin is approximately 87%. Since co-administration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food.
Distribution: 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%).
Metabolism: 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.
Elimination: 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 t1/2 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.
Characteristics in Patients: Renal Impairment: A single-dose, open-label study was conducted to evaluate the pharmacokinetics of JANUVIA (50-mg dose) in patients with varying degrees of chronic renal impairment compared to normal healthy control subjects. The study included patients with mild, moderate, and severe renal impairment, as well as patients with ESRD on hemodialysis. In addition, the effects of renal impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate or severe renal impairment (including ESRD) were assessed using population pharmacokinetic analyses.
Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (eGFR ≥60 mL/min/1.73 m2 to <90 mL/min/1.73 m2) and patients with moderate renal impairment (eGFR ≥45 mL/min/1.73 m2 to <60 mL/min/1.73 m2), respectively. Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is not necessary.
Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m2 to <45 mL/min/1.73 m2), and approximately 4-fold in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), including patients with ESRD on hemodialysis. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with eGFR <45 mL/min/1.73 m2 (see Patients with Renal Impairment under Dosage & Administration).
Hepatic Impairment: 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 JANUVIA. These differences are not considered to be clinically meaningful. No dosage adjustment for JANUVIA is necessary for patients with mild or moderate hepatic impairment.
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.
Elderly: No dosage adjustment is required based on age. 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.
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.
Gender: No dosage adjustment is necessary based on gender. 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.
Race: No dosage adjustment is necessary based on race. 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.
Body Mass Index (BMI): No dosage adjustment is necessary based on BMI. 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.
Type 2 Diabetes: The pharmacokinetics of sitagliptin in patients with type 2 diabetes are generally similar to those in healthy subjects.
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