Pharmacology: Mechanism of Action:
Sitagliptin 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 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. 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.
In patients with type 2 diabetes, administration of sitagliptin led to inhibition of 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 GLP-1 and 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.
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 was observed at 3 hrs post-dose and was 8 msec. This increase is not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11-fold 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.
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 1-4 hrs 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 microM·hr, Cmax
was 950 nM and apparent terminal half-life was 12.4 hrs. Plasma AUC of sitagliptin increased approximately 14% following 100-mg doses at steady-state compared to the 1st dose. The intrasubject and intersubject 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.
The absolute bioavailability of sitagliptin is approximately 87%. Because co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or without food.
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%).
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 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.
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 half-life 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, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
Special Populations: Renal Insufficiency:
A single dose, open-label study was conducted to evaluate the pharmacokinetics of sitagliptin (50-mg dose) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control subjects. The study included patients with renal insufficiency classified on the basis of creatinine clearance as mild (50 to <80 mL/min), moderate (30 to <50 mL/min) and severe (<30 mL/min), as well as patients with ESRD on hemodialysis. In addition, the effects of renal insufficiency on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild or moderate renal insufficiency were assessed using population pharmacokinetic analyses. Creatinine clearance was measured by 24-hr urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula:
CrCl = [140 - age (years)] x weight (kg) / [72 x serum creatinine (mg/dL)] x 0.85 for female patients
Compared to normal healthy control subjects, an approximate 1.1- to 1.6-fold increase in plasma AUC of sitagliptin was observed in patients with mild renal insufficiency. Because increases of this magnitude are not clinically relevant, dosage adjustment in patients with mild renal insufficiency is not necessary. Plasma AUC levels of sitagliptin were increased approximately 2-fold and 4-fold in patients with moderate renal insufficiency and in patients with severe renal insufficiency, including patients with ESRD on hemodialysis, respectively. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hr hemodialysis session starting 4 hrs post-dose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring hemodialysis. (See Dosage & Administration.)
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. No dosage adjustment for sitagliptin is necessary for patients with mild or moderate hepatic insufficiency.
There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
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.
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.
No dosage adjustment is required based solely on age. 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.
Studies characterizing the pharmacokinetics of sitagliptin in pediatric patients have not been performed.
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 available pharmacokinetic data, including subjects of White, Hispanic, Black, Asian and other racial groups.
Drug Interactions: 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: Effects of Sitagliptin on Other Drugs:
In clinical studies, as described as follows, 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 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax
Co-administration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.
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. However, the risk of hypoglycemia from the co-administration of sitagliptin and sulfonylureas is unknown.
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 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.
Effects of Other Drugs on Sitagliptin:
Clinical data described as follows suggest that sitagliptin is not susceptible to clinically meaningful interactions by co-administered medications: Metformin: Co-administration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
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: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility:
A 2-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 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 of 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 comparison).
There were 2316 patients with type 2 diabetes randomized in 4 double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of sitagliptin on glycemic control. In these studies, the mean age of patients was 54.8 years, and 62% of patients were White, 18% were Hispanic, 6% were Black, 9% were Asian and 4% were of other racial groups.
In patients with type 2 diabetes, treatment with Januvia produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hr post-prandial glucose (PPG) compared to placebo.
A total of 1262 patients with type 2 diabetes participated in 2 double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of Januvia monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise and drug washout period of about 7 weeks. Patients with inadequate glycemic control (A1C 7-10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7-10%) were randomized after completing the 2-week single-blind placebo run-in period. In the 18-week study, 521 patients were randomized to placebo, Januvia 100 mg or Januvia 200 mg, and in the 24-week study, 741 patients were randomized to placebo, Januvia 100 mg or Januvia 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or Januvia.
Treatment with Januvia at 100 mg daily provided significant improvements in A1C, FPG and 2-hr PPG compared to placebo (see Table 1). In the 18-week study, 9% of patients receiving Januvia 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving Januvia 100 mg and 21% of patients receiving placebo required rescue therapy. The improvement in A1C was not affected by gender, age, race or baseline BMI. As is typical for trials of agents to treat type 2 diabetes, mean response to Januvia in A1C-lowering appears to be related to the degree of A1C elevation at baseline. 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. (See Table 1.)
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Additional Monotherapy Study:
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. A small increase in serum creatinine was reported in patients with moderate renal insufficiency treated with Januvia relative to those on placebo. In addition, the reductions in A1C and FPG with Januvia compared to placebo were generally similar to those observed in other monotherapy studies. (See Pharmacology under Actions.)
Combination Therapy: 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. 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 100 mg of Januvia 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, Januvia provided significant improvements in A1C, FPG and 2-hr PPG compared to placebo with metformin (see Table 2). Rescue glycemic therapy was used in 5% of patients treated with Januvia 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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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. Patients on any oral antihyperglycemic agent in monotherapy (N=212) or on a PPARγ agent in combination therapy (N=106) or not on an antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg/day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured included A1C and fasting glucose.
In combination with pioglitazone, Januvia provided significant improvements in A1C and FPG compared to placebo with pioglitazone (see Table 3). Rescue therapy was used in 7% of patients treated with Januvia 100 mg and 14% of patients treated with placebo. There was no significant difference between Januvia and placebo in body weight change. (See Table 3.)
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