Pharmacology: Mechanism of action: Dapagliflozin/sitagliptin combination: SIDAPVIA combines the sodium glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and the dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin with distinct and complementary mechanisms of action to improve glycaemic control. The combination of both agents delivers clinically meaningful reductions in haemoglobin A1c (HbA1c) for improved glycaemic control in patients with type 2 diabetes mellitus. While sitagliptin has a neutral effect on weight, urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with weight loss.
Dapagliflozin: Dapagliflozin is a highly potent, selective, and reversible inhibitor of sodium glucose cotransporter 2 (SGLT2) that improves glycaemic control in patients with diabetes mellitus and provides cardio renal benefits.
Inhibition of SGLT2 by dapagliflozin reduces reabsorption of glucose from the glomerular filtrate in the proximal renal tubule with a concomitant reduction in sodium reabsorption leading to urinary excretion of glucose and osmotic diuresis. Dapagliflozin therefore increases the delivery of sodium to the distal tubule which increases tubuloglomerular feedback and reduces intraglomerular pressure. This combined with osmotic diuresis leads to a reduction in volume overload, reduced blood pressure, and lower preload and afterload, which may have beneficial effects on cardiac remodelling and diastolic function, and preserve renal function. Other effects include an increase in haematocrit and reduction in body weight.
Dapagliflozin improves both fasting and postprandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary excretion of excess glucose. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24-hour dosing interval, and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Thus, in subjects with normal blood glucose and/or low GFR, dapagliflozin has a low propensity to cause hypoglycaemia, as the amount of filtrated glucose is small and can be reabsorbed by SGLT1 and unblocked SGLT2 transporters. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Over time, improvement in beta-cell function (HOMA-2) has been observed in clinical studies with dapagliflozin.
The majority of weight reduction is body-fat loss, including visceral fat, rather than lean tissue, or fluid loss as demonstrated by dual energy x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI).
SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is greater than 1400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.
Sitagliptin: 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 beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha 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.
Pharmacodynamics: General: Dapagliflozin: Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in patients with type 2 diabetes mellitus for 12 weeks. This glucose elimination rate approached the maximum glucose excretion observed at 20 mg/day of dapagliflozin. Evidence of sustained glucose excretion was seen in patients with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years.
This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in urinary volume. Urinary volume increases in patients with type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 mL/day. The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations.
Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by a reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from 0.33 mg/dL to 0.87 mg/dL.
Sitagliptin: In a two-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. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations.
Clinical trial information: Clinical efficacy: Treatment with dapagliflozin added on to sitagliptin (with or without metformin), in type 2 diabetes mellitus patients, produced clinically relevant and statistically significant improvements in mean change from baseline at Week 24 in HbA1c and fasting plasma glucose (FPG) compared to control. Additionally, a clinically relevant and statistically significant reduction in mean change from baseline in body weight was seen at Week 24. In a dedicated clinical study of dapagliflozin to evaluate body composition, decrease in weight was mainly attributable to a reduction in body fat mass as measured by DXA.
In two studies of dapagliflozin 10 mg in type 2 diabetes mellitus patients with hypertension, statistically significant reductions in mean seated systolic blood pressure (SBP) were seen in patients treated with dapagliflozin 10 mg combined with other oral antidiabetic and antihypertensive treatments (an angiotensin converting enzyme inhibitor [ACEi] or angiotensin receptor blocker [ARB] in one study and an ACEi or ARB plus one additional antihypertensive treatment in another study) compared to those treated with placebo at Week 12.
Glycaemic control: Add on of dapagliflozin to sitagliptin alone or in combination with metformin: A total of 452 patients with type 2 diabetes who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in this 24-week, placebo-controlled study with a 24-week extension period to evaluate dapagliflozin co-administered with sitagliptin (a DPP4 inhibitor) with or without metformin.
Eligible patients were stratified based on the presence or absence of background metformin (≥1500 mg/day) and within each stratum were randomized to either dapagliflozin 10 mg plus sitagliptin 100 mg once daily or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for dapagliflozin 10 mg versus placebo for the total study group (sitagliptin with or without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin). Thirty seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% were on a DPP4 inhibitor plus metformin. Dose titration of dapagliflozin, sitagliptin or metformin was not permitted during the study.
Co-administered with sitagliptin (with and without metformin), dapagliflozin 10 mg provided significant improvements in HbA1c, HbA1c in patients with baseline HbA1c ≥8%, FPG, and body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (Table 1). These improvements were also seen in the stratum of patients who received dapagliflozin 10 mg plus sitagliptin alone (n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received dapagliflozin 10 mg plus sitagliptin and metformin (n=113) compared with placebo plus sitagliptin with metformin (n=113).
At Week 48, adjusted mean change from baseline in HbA1c, HbA1c in patients with HbA1c ≥8% at baseline, FPG, PPG, and body weight were -0.30%, -0.72%, -19.7 mg/dL, -43.0 mg/dL, and -2.03 kg, respectively, for patients treated with dapagliflozin 10 mg plus sitagliptin with or without metformin, and 0.38%, 0.26%, 13.5 mg/dL, -12.1 mg/dL, and 0.18 kg for patients treated with placebo plus sitagliptin with or without metformin based on the longitudinal repeated measures analysis excluding data after rescue. At Week 48, for the stratum of patients without metformin, adjusted mean change from baseline in HbA1c for patients treated with dapagliflozin 10 mg plus sitagliptin was 0.00% and placebo plus sitagliptin was 0.85%; and the stratum of patients with metformin, adjusted mean change from baseline in HbA1c for patients treated with dapagliflozin 10 mg plus sitagliptin was -0.44% and placebo plus sitagliptin was 0.15% based on the longitudinal repeated measures analysis excluding data after rescue.
The proportion of patients at Week 24 and Week 48 who were rescued or discontinued for lack of glycemic control (adjusted for baseline HbA1c) was higher on sitagliptin with or without metformin (40.5% and 56.5%, respectively) than on dapagliflozin plus sitagliptin with or without metformin (19.5% and 32.6%, respectively). (See Table 1.)
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Glycaemic control in special populations: Use in patients with type 2 diabetes mellitus and renal impairment: Dapagliflozin: The glycaemic efficacy and safety of dapagliflozin was evaluated in a dedicated study of patients with eGFR ≥45 to <60 mL/min/1.73 m
2.
In this randomized, double blind, placebo-controlled trial a total of 321 adult patients with type 2 diabetes mellitus and eGFR ≥45 to <60 mL/min/1.73 m
2 (moderate renal impairment subgroup CKD 3A), with inadequate glycaemic control on current treatment regimen, were treated with dapagliflozin 10 mg or placebo. At Week 24, dapagliflozin 10 mg (n=159) provided significant improvements in HbA1c, FPG, body weight and SBP compared with placebo (n=161) (Table 2). The mean change from baseline in HbA1c and the placebo-corrected mean HbA1c change was -0.37% and -0.34%, respectively. The mean change from baseline in FPG and the placebo corrected mean FPG was -21.46 mg/dL and -16.59 mg/dL, respectively. The mean body weight reduction (percentage) and the placebo corrected mean body weight reduction was -3.42% and -1.43%, respectively. The mean reduction in seated SBP and the placebo-corrected mean reduction in seated SBP was -4.8 mmHg and -3.1 mmHg, respectively. (See Table 2.)
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The safety profile of dapagliflozin in the study was consistent with that in the general population of patients with type 2 diabetes mellitus. Mean eGFR decreased initially during the treatment period in the dapagliflozin group and subsequently remained stable during the 24-week treatment period (dapagliflozin: -3.39 mL/min/1.73 m
2 and placebo: -0.90 mL/min/1.73 m
2). At 3 weeks after termination of dapagliflozin, the mean change from baseline in eGFR in the dapagliflozin group was similar to the mean change in the placebo group (dapagliflozin: 0.57 mL/min/1.73 m
2 and placebo: -0.04 mL/min/1.73 m
2).
Supportive study: Dapagliflozin dual energy X-ray absorptiometry in patients with type 2 diabetes mellitus: Due to the mechanism of action of dapagliflozin, a study was done to evaluate body composition and bone mineral density in 182 patients with type 2 diabetes mellitus. Treatment with dapagliflozin 10 mg added on to metformin over a 24-week period provided significant improvements compared with placebo plus metformin, respectively, in body weight (mean change from baseline: -2.96 kg versus -0.88 kg); waist circumference (mean change from baseline: -2.51 cm versus -0.99 cm), and body-fat mass as measured by DXA (mean change from baseline: -2.22 kg versus -0.74 kg) rather than lean tissue or fluid loss. Dapagliflozin plus metformin treatment showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment (change from baseline: -322.6 cm
3 versus -8.7 cm
3) in an MRI substudy. Week 24 was analysed using last observation carried forward (LOCF) analysis including data after rescue.
The improvements in body weight, waist circumference, body-fat mass and visceral adipose tissue observed at Week 24 were sustained at Week 50 and Week 102. There was no change in bone mineral density in either treatment group up to Week 102 (mean decrease from baseline for all anatomical regions <1.0%).
Cardiovascular and Renal Outcomes studies in patients with type 2 diabetes mellitus: Dapagliflozin: Dapagliflozin Effect on Cardiovascular Events (DECLARE) was an international, multicenter, randomized, double-blind, placebo-controlled clinical study conducted to determine the effect of FORXIGA compared with placebo on CV outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either at least two additional CV risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidemia, hypertension or current tobacco use) or established CV disease.
Of 17,160 randomized patients, 6,974 (40.6%) had established CV disease and 10,186 (59.4%) did not have established CV disease. 8,582 patients were randomized to FORXIGA 10 mg and 8,578 to placebo and were followed for a median of 4.2 years.
The mean age of the study population was 63.9 years, 37.4% were female. In total, 22.4% had diabetes for ≤5 years, mean duration of diabetes was 11.9 years. Mean HbA1c was 8.3% and mean BMI was 32.1 kg/ m
2.
At baseline, 10.0% of patients had a history of heart failure. Mean eGFR was 85.2 mL/min/1.73 m
2, 7.4% of patients had eGFR <60mL/min/1.73 m
2 and 30.3% of patients had micro- or macroalbuminuria (urine albumin to creatinine ratio [UACR] ≥30 to ≤300 mg/g or >300 mg/g, respectively).
Most patients (98%) used one or more diabetic medications at baseline, including metformin (82%), insulin (41%) and sulfonylurea (43%).
The primary endpoints were time to first event of the composite of CV death, myocardial infarction or ischaemic stroke (MACE) and time to first event of the composite of hospitalization for heart failure or CV death. The secondary endpoints were a renal composite endpoint and all-cause mortality.
Major Adverse Cardiovascular Events: Dapagliflozin 10 mg demonstrated non-inferiority versus placebo for the composite of CV death, myocardial infarction or ischemic stroke (one-sided p <0.001).
Heart Failure or Cardiovascular Death: Dapagliflozin 10 mg demonstrated superiority versus placebo in preventing the composite of hospitalization for heart failure or CV death (Figure 1). The difference in treatment effect was driven by hospitalization for heart failure, with no difference in CV death (Figure 2).
The treatment benefit of FORXIGA over placebo was observed both in patients with and without established CV disease, with and without heart failure at baseline, and was consistent across key subgroups, including age, gender, renal function (eGFR), and region. (See Figure 1.)
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Results on primary and secondary endpoints are displayed in Figure 2. Superiority of dapagliflozin over placebo was not demonstrated for MACE (p=0.172). The renal composite endpoint and all-cause mortality were therefore not tested as part of the confirmatory testing procedure. (See Figure 2.)
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Nephropathy: Dapagliflozin reduced the incidence of events of the composite of confirmed sustained eGFR decrease, ESKD, renal or CV death. The difference between groups was driven by reductions in events of the renal components; sustained eGFR decrease, ESKD and renal death (Figure 2).
The hazard ratio for time to nephropathy (sustained eGFR decrease, end-stage renal disease and renal death) was 0.53 (95% CI 0.43, 0.66) for dapagliflozin versus placebo.
In addition, Dapagliflozin reduced the new onset of sustained albuminuria (hazard ratio 0.79 [95% CI 0.72, 0.87]) and led to greater regression of macroalbuminuria (hazard ratio 1.82 [95% CI 1.51, 2.20]) compared with placebo.
Sitagliptin: The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was a randomised study in 14671 patients in the intention to treat population with an HbA1c of ≥6.5 to 8.0% with established CV disease who received sitagliptin (7332) 100 mg daily (or 50 mg daily if the baseline eGFR was ≥30 and <50 mL/min/1.73 m
2) or placebo (7339) added to usual care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR <30 mL/min/1.73 m
2 were not to be enrolled in the study. The study population included 2004 patients ≥75 years of age and 3324 patients with renal impairment (eGFR <60 mL/min/1.73 m
2).
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.
The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for unstable angina. Secondary cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal 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, sitagliptin, when added to usual care, did not increase the risk of major adverse cardiovascular events or the risk of hospitalisation for heart failure compared to usual care without sitagliptin in patients with type 2 diabetes mellitus (see Table 3).
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Clinical safety: Events related to decreased renal function - dapagliflozin: In the 13-study, short-term, placebo-controlled pool, mean serum creatinine levels increased a small amount at Week 1 (mean change from baseline: 0.041 mg/dL dapagliflozin 10 mg versus 0.008 mg/dL placebo) and decreased toward baseline by Week 24 (mean change from baseline: 0.019 mg/dL dapagliflozin 10 mg versus 0.008 mg/dL placebo). There were no further changes through Week 102.
In the DECLARE study, there were fewer patients with marked laboratory abnormalities of creatinine, creatinine clearance, eGFR, and UACR in the dapagliflozin group compared with the placebo group. Fewer renal events (e.g., decreased renal creatinine clearance, renal impairment, increased blood creatinine, and decreased glomerular filtration rate) were reported in the dapagliflozin group compared with the placebo group: 422 (4.9%) and 526 (6.1%), respectively. There were fewer patients with events reported as acute kidney injury in the dapagliflozin group compared with the placebo group: 125 (1.5%) and 175 (2.0%), respectively. There were fewer patients with SAEs of renal events in the dapagliflozin group compared with the placebo group: 80 (0.9%) and 136 (1.6%), respectively.
Laboratory findings - dapagliflozin: Haematocrit: In the pool of 13 placebo-controlled studies, increases from baseline in mean haematocrit values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in haematocrit were 2.30% in the dapagliflozin 10 mg group versus -0.33% in the placebo group. At Week 102, the mean changes were 2.68% versus -0.46%, respectively. By Week 24, haematocrit values >55% were reported in 1.3% of dapagliflozin 10 mg-treated patients versus 0.4% of placebo treated patients. Results were similar during the short-term plus long-term phase (the majority of patients were exposed to treatment for more than one year).
Serum inorganic phosphorus: In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin 10 mg-treated patients compared with placebo-treated patients (mean increases of 0.13 mg/dL versus -0.04 mg/dL, respectively). Similar results were seen at Week 102. Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL if age 17 65 or ≥5.1 mg/dL if age ≥66) were reported in dapagliflozin 10 mg group versus placebo at Week 24 (1.7% versus 0.9%, respectively) and during the short-term plus long-term phase (3.0% versus 1.6%, respectively). The clinical relevance of these findings is unknown.
Lipids: In the pool of 13 placebo-controlled studies, small changes from baseline in mean lipid values were reported at Week 24 in dapagliflozin 10 mg-treated patients compared with placebo-treated patients. Mean percent change from baseline at Week 24 for dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.5% versus 0.0%; high density lipoprotein (HDL) cholesterol, 6.0% versus 2.7%; low density lipoprotein (LDL) cholesterol, 2.9% versus -1.0%; triglycerides, -2.7% versus -0.7%. Mean percent change from baseline at Week 102 for dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.1% versus -1.5%; HDL cholesterol, 6.6% versus 2.1%; LDL cholesterol, 2.9% versus -2.2%; triglycerides, -1.8% versus -1.8%. The ratio between LDL cholesterol and HDL cholesterol decreased for both treatment groups at Week 24.
In the DECLARE study, no clinical important differences in total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides were seen.
Pharmacokinetics: Dapagliflozin/sitagliptin combination: SIDAPVIA 10mg/100mg tablets are considered to be bioequivalent to co-administration of corresponding doses of dapagliflozin and sitagliptin administered together as single dose individual tablets in healthy subjects in fasted state.
Absorption: Dapagliflozin: Dapagliflozin is rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (C
max) are usually attained within 2 hours after administration in the fasted state. The C
max and AUC values increase proportionally to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food has relatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. Administration with a high-fat meal decreases dapagliflozin C
max by up to 50% and prolonged T
max by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.
Sitagliptin: The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or without food.
Distribution: Dapagliflozin: Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in various disease states (e.g., renal or hepatic impairment).
Sitagliptin: The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metabolism: Dapagliflozin: Dapagliflozin is a C-linked glucoside, meaning the aglycone component is attached to glucose by a carbon bond, thereby conferring stability against glucosidase enzymes. The mean plasma terminal half-life (t
1/2) for dapagliflozin is 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounts for 61% of a 50 mg [
14C]-dapagliflozin dose and is the predominant drug-related component in human plasma, accounting for 42% (based on AUC [0-12 hour]) of total plasma radioactivity, similar to the 39% contribution by parent drug. Based on AUC, no other metabolite accounts for >5% of the total plasma radioactivity. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP-mediated metabolism is a minor clearance pathway in humans.
Sitagliptin: Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
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: Dapagliflozin: Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin. After administration of 50 mg [
14C]-dapagliflozin dose, 96% is recovered; 75% in urine and 21% in faeces. In faeces, approximately 15% of the dose is excreted as parent drug.
Sitagliptin: 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 t
1/2 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.
Special populations: Renal impairment: Dapagliflozin: At steady-state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment (as determined by iohexol clearance) had mean systemic exposures of dapagliflozin that were 32%, 60%, and 87% higher, respectively, than those of patients with type 2 diabetes mellitus and normal renal function. At dapagliflozin 20 mg once-daily, higher systemic exposure to dapagliflozin in patients with type 2 diabetes mellitus and renal impairment did not result in a correspondingly higher renal-glucose clearance or 24-hour glucose excretion. The renal-glucose clearance and 24-hour glucose excretion were lower in patients with moderate or severe renal impairment as compared to patients with normal and mild renal impairment. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function, and 85, 52, 18, and 11 g of glucose/day was excreted by patients with type 2 diabetes mellitus and normal renal function or mild, moderate, or severe renal impairment, respectively. There were no differences in the protein binding of dapagliflozin between renal impairment groups or compared to healthy subjects. The impact of haemodialysis on dapagliflozin exposure is not known.
Sitagliptin: Compared to normal healthy control subjects, plasma AUC of sitagliptin (50 mg) was increased by approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR ≥60 to <90 mL/min) and patients with moderate renal impairment (GFR ≥45 to <60 mL/min), 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 (GFR ≥30 to <45 mL/min), and approximately 4-fold in patients with severe renal impairment (GFR <30 mL/min), including in patients with ESKD on haemodialysis. Sitagliptin was modestly removed by haemodialysis (13.5% over a 3- to 4-hour haemodialysis session starting 4 hours post dose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR <45 mL/min.
Hepatic impairment: Dapagliflozin: A single-dose (10 mg) dapagliflozin clinical pharmacology study was conducted in patients with mild, moderate, or severe hepatic impairment (Child-Pugh classes A, B, and C, respectively) and healthy matched controls in order to compare the pharmacokinetic characteristics of dapagliflozin between these populations. There were no differences in the protein binding of dapagliflozin between patients with hepatic impairment compared to healthy subjects. In patients with mild or moderate hepatic impairment, mean C
max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful and no dose adjustment from the proposed usual dose of 10 mg once daily for dapagliflozin is proposed for these populations. In patients with severe hepatic impairment (Child-Pugh class C) mean C
max and AUC of dapagliflozin were up to 40% and 67% higher than matched healthy controls, respectively.
SIDAPVIA should not be used in patients with severe hepatic impairment.
Sitagliptin: No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment (Child-Pugh score ≤9). 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.
Age: Dapagliflozin: No dosage adjustment for dapagliflozin from the dose of 10 mg once daily is recommended on the basis of age.
The effect of age (young: ≥18 to <40 years [n=105] and elderly: ≥65 years [n=224]) was evaluated as a covariate in a population pharmacokinetic model and compared to patients ≥40 to <65 years using data from healthy subject and patient studies). The mean dapagliflozin systemic exposure (AUC) in young patients was estimated to be 10.4% lower than in the reference group (90% CI; 87.9, 92.2%) and 25% higher in elderly patients compared to the reference group (90% CI; 123, 129%). These differences in systemic exposure were considered to not be clinically meaningful.
Sitagliptin: No dose 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 1 and Phase 2 data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Paediatric and adolescent patients: SIDAPVIA is not indicated in paediatric and adolescent patients (see Dosage & Administration).
Gender: Dapagliflozin: No dosage adjustment from the dose of 10 mg once daily is recommended for dapagliflozin on the basis of gender. Gender was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. The mean dapagliflozin AUCss in females (n=619) was estimated to be 22% higher than in males (n=634) (90% CI; 117,124).
Sitagliptin: Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase 1 pharmacokinetic data and on a population pharmacokinetic analysis of Phase 1 and Phase 2 data.
Race: Dapagliflozin: No dosage adjustment from the dapagliflozin dose of 10 mg once daily is recommended on the basis of race. Race (White, Black, or Asian) was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. Differences in systemic exposures between these races were small. Compared to Whites (n=1147), Asian subjects (n=47) had no difference in estimated mean dapagliflozin systemic exposures (90% CI range; 3.7% lower, 1% higher). Compared to Whites, Black subjects (n=43) had 4.9% lower estimated mean dapagliflozin systemic exposures (90% CI range; 7.7% lower, 3.7% lower).
Sitagliptin: Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase 1 pharmacokinetic data and on a population pharmacokinetic analysis of Phase 1 and Phase 2 data.
Body weight: Dapagliflozin: In a population pharmacokinetic analysis using data from healthy subject and patient studies, systemic exposures in high-body-weight subjects (≥120 kg, n=91) were estimated to be 78.3% (90% CI; 78.2, 83.2%) of those of reference subjects with body weight between 75 and 100 kg. This difference is considered to be small, therefore, no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with high body weight (≥120 kg) is recommended.
Subjects with low body weights (<50 kg) were not well represented in the healthy subject and patient studies used in the population pharmacokinetic analysis. Therefore, dapagliflozin systemic exposures were simulated with a large number of subjects. The simulated mean dapagliflozin systemic exposures in low-body-weight subjects were estimated to be 29% higher than subjects with the reference group body weight. This difference is considered to be small, and based on these findings, no dose adjustment from the proposed dose of 10 mg dapagliflozin once daily in type 2 diabetes mellitus patients with low body weight (<50 kg) is recommended.
Sitagliptin: BMI had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase 1 pharmacokinetic data and on a population pharmacokinetic analysis of Phase 1 and Phase 2 data.
Toxicology: Preclinical safety data: Dapagliflozin/sitagliptin combination: No animal studies have been conducted with the combination of dapagliflozin and sitagliptin. The following data are based on the findings from separate nonclinical studies on dapagliflozin and sitagliptin, respectively.
Carcinogenesis, mutagenesis, impairment of fertility: Dapagliflozin: Dapagliflozin did not induce tumours in either mice or rats at any of the doses evaluated in 2 year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were equivalent to AUC exposure multiples of approximately 72× (males) and 105× (females) the human AUC at MRHD of 10 mg/day. In rats, AUC exposures were approximately 131× (males) and 186× (females) the human AUC at the MRHD.
Dapagliflozin was negative in the Ames mutagenicity assay and was positive in an in vitro clastogenicity assay, but only in the presence of S9 activation and at concentrations ≥100 μg/mL. Importantly, dapagliflozin was negative for clastogenicity in vivo in a series of studies evaluating micronuclei or DNA repair in rats at exposure multiples >2100× the human exposure at the MRHD. These studies, along with the absence of tumour findings in the rat and mouse carcinogenicity studies, support that dapagliflozin does not represent a genotoxic risk to humans.
In a study of fertility and early embryonic development in rats, doses of 15, 75, or 300/210 mg/kg/day dapagliflozin were administered to males (the 300 mg/kg/day dose was lowered to 210 mg/kg/day after 4 days), and doses of 3, 15, or 75 mg/kg/day were administered to females. Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated males or females at any dose tested (at exposure multiples ≤1708× and 998× the MRHD in males and females, respectively). However, at 300/210 mg/kg/day, seminal vesicle and epididymal weights were reduced; sperm motility and sperm counts were reduced; and there were low numbers of morphologically abnormal sperm.
Sitagliptin: A two-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 two-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 micronucleus assay.
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).
Teratogenicity and impairment of early development: Dapagliflozin: Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy and lactation (time periods corresponding to the second and third trimesters of pregnancy with respect to human renal maturation) are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny.
In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, renal pelvic and tubular dilatations were reported at all dose levels; pup exposures at the lowest dose tested were ≥15× the MRHD. These findings were associated with dose-related increases in kidney weight and macroscopic kidney enlargement observed at all doses. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period.
In a separate study of prenatal and postnatal development, maternal rats were dosed from gestation day (GD) 6 through PND 21 (also at 1, 15, or 75 mg/kg/day), and pups were indirectly exposed in utero and throughout lactation. (A satellite study was conducted to assess dapagliflozin exposures in milk and pups). Increased incidence or severity of renal pelvic dilatation was again observed in adult offspring of treated dams, although only at 75 mg/kg/day (associated maternal and pup dapagliflozin exposures were 1415× and 137×, respectively, the human values at the MRHD). Additional developmental toxicity was limited to dose-related reductions in pup body weights and observed only at doses ≥15 mg/kg/day (associated with pup exposures that are ≥29× the human values at the MRHD). Maternal toxicity was evident only at 75 mg/kg/day and limited to transient reductions in body weight and food consumption at dose initiation. The no-adverse-effect level (NOAEL) for developmental toxicity, 1 mg/kg/day, is associated with a maternal systemic exposure multiple that is approximately 19× the human value at the MRHD.
In additional studies of embryo-foetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the major periods of organogenesis in each species. Neither maternal nor developmental toxicities were observed in rabbits at any dose tested (20, 60, or 180 mg/kg/day); 180 mg/kg/day is associated with a systemic exposure multiple of approximately 1191× the MRHD. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441× the MRHD). Doses ≥150 mg/kg/day (≥2344× the human values at the MRHD) were associated with both maternal and developmental toxicities. Maternal toxicity included mortality, adverse clinical signs, and decrements in body weight and food consumption. Developmental toxicity consisted of increased embryo-foetal lethality, increased incidences of foetal malformations and skeletal variations, and reduced foetal body weights. Malformations included a low incidence of great vessel malformations, fused ribs and vertebral centra, and duplicated manubria and sternal centra. Variations were primarily reduced ossifications.
Animal toxicology: Dapagliflozin: Most of the effects observed in pivotal repeat-dose toxicity studies in both rats and dogs were considered to be secondary to pharmacologically mediated increases in urinary glucose, and included decreases in body weights and/or body weight gains, increased food consumption, and increases in urine volumes due to osmotic diuresis. Dapagliflozin was well tolerated when given orally to rats for up to 6 months at doses of ≤25 mg/kg/day (≥346× the human exposures at the MRHD) and in dogs for up to 12 months at doses of ≤120 mg/kg/day (≥3200× the human exposures at the MRHD). Also, single-dose studies with dapagliflozin indicated that the dapagliflozin 3-O-glucuronide metabolite would have been formed in both rat and dog toxicity studies at exposure levels (AUCs) that are greater than, or approximately equal to, anticipated human dapagliflozin 3-O-glucuronide exposures following administration of dapagliflozin at the MRHD. In rats, the most noteworthy nonclinical toxicity finding of increased trabecular bone and tissue mineralization (associated with increased serum calcium) was only observed at high-exposure multiples (≥2100× based on human exposures at the MRHD). Despite achieving exposure multiples of ≥3200× the human exposure at the MRHD, there was no dose-limiting or target-organ toxicities identified in the 12-month dog study.
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