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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.
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 1,400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.
Sitagliptin (This information is based on studies related to the innovator of Sitagliptin): Sitagliptin is an oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP4) inhibitors. The improvement in glycaemic control observed with this medicinal product may be mediated 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 signalling pathways involving cyclic AMP. Treatment with GLP-1 or with DPP4 inhibitors in animal models of type 2 diabetes mellitus 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 hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP4 enzyme, which rapidly hydrolyses the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP4, 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 mellitus with hyperglycaemia, these changes in insulin and glucagon levels lead to lower HbA1c and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes mellitus and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP4 and does not inhibit the closely-related enzymes DPP8 or DPP9 at therapeutic concentrations.
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 (This information is based on studies related to the innovator of 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. Co-administration 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.
Glycaemic control: Add-on of dapagliflozin to sitagliptin alone or in combination with metformin: A total of 452 patients with type 2 diabetes mellitus who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycaemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in a 24-week, placebo-controlled study with a 24-week extension period to evaluate dapagliflozin in combination with sitagliptin with or without metformin.
Eligible patients were stratified based on the presence or absence of background metformin (≥1,500 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.
The mean age of the total study population was 54.9 years (18% ≥65 years of age), mean body mass index (BMI) was 32.40 kg/m2 and 54.8% were male. The mean duration of type 2 diabetes mellitus was 5.67 years and the mean baseline HbA1c was 7.93% (HbA1c was slightly lower in patients using metformin [7.83%] than in patients not using metformin [8.03%]).
In combination with sitagliptin (with or without metformin), dapagliflozin 10 mg provided significant improvements in HbA1c, HbA1c in patients with baseline HbA1c ≥8%, FPG, and significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24. 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 in the stratum of patients who received dapagliflozin 10 mg plus sitagliptin with metformin (n=113) compared with placebo plus sitagliptin with metformin (n=113). Results on primary and key secondary endpoints are displayed in Table 2.
The proportion of patients achieving HbA1c <7% was higher in the dapagliflozin plus sitagliptin (with or without metformin) group (28.3%) compared to the placebo plus sitagliptin (with or without metformin) group (19.4%) at Week 24, using last observation carried forward (LOCF) analysis excluding data after rescue. Nominal p<0.05, for the difference between treatment groups.
The adjusted mean change from baseline in seated SBP in the full study population was -1.8 mmHg in the dapagliflozin plus sitagliptin (with or without metformin) group and 0.8 mmHg in the placebo plus sitagliptin (with or without metformin) group at Week 24, using last observation carried forward (LOCF) analysis including data after rescue. Nominal p<0.05, for the difference between treatment groups.
At Week 48, based on the longitudinal repeated measures analysis excluding data after rescue, adjusted mean change from baseline in HbA1c, HbA1c in patients with HbA1c ≥8% at baseline, FPG, 2-hour postprandial glucose (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. The mean reduction from baseline in HbA1c for patients treated with dapagliflozin 10 mg plus sitagliptin, compared with patients treated with placebo plus sitagliptin was 0.68% (nominal p<0.0001) 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 for 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%.
The proportion of patients at Week 24 and Week 48 who were rescued or discontinued for lack of glycaemic control (adjusted for baseline HbA1c) was higher for sitagliptin with or without metformin (40.5% and 56.5%, respectively) than for dapagliflozin plus sitagliptin with or without metformin (19.5% and 32.6%, respectively). (See Table 1.)
Click on icon to see table/diagram/imageFor efficacy and safety results from individual clinical studies of dapagliflozin and sitagliptin, refer to the information in the SPC for either dapagliflozin or sitagliptin.
Glycaemic control in special populations: Use in patients with type 2 diabetes mellitus and hypertension Dapagliflozin: In a pre-specified pooled analysis of 13 placebo-controlled studies, treatment with dapagliflozin 10 mg resulted in a systolic blood pressure change from baseline of -3.7 mmHg and diastolic blood pressure of -1.8 mmHg versus -0.5 mmHg systolic and -0.5 mmHg diastolic blood pressure for placebo group at week 24. Similar reductions were observed up to 104 weeks.
In two 12-week, placebo-controlled studies a total of 1,062 patients with inadequately controlled type 2 diabetes and hypertension (despite pre-existing stable treatment with an ACE-I or ARB in one study and an ACE-I or ARB plus one additional antihypertensive treatment in another study) were treated with dapagliflozin 10 mg or placebo. At week 12 for both studies, dapagliflozin 10 mg plus usual antidiabetic treatment provided improvement in HbA1c and decreased the placebo-corrected systolic blood pressure on average by 3.1 and 4.3 mmHg, respectively.
In a dedicated study in diabetic patients with an eGFR ≥45 to <60 mL/min/1.73 m2, treatment with dapagliflozin demonstrated reductions in seated systolic blood pressure at week 24:-4.8 mmHg compared to -1.7 mmHg for placebo (p <0.05).
Use in patients with type 2 diabetes mellitus and renal impairment Dapagliflozin: Moderate renal impairment CKD 3A (eGFR ≥45 to <60 mL/min/1.73 m2) The efficacy of dapagliflozin was assessed in a dedicated study in diabetic patients with an eGFR ≥45 to <60 mL/min/1.73 m2 who had inadequate glycaemic control on usual care. Treatment with dapagliflozin resulted in reductions in HbA1c and body weight compared with placebo. (See Table 2.)
Click on icon to see table/diagram/imageClinical safety: Events related to decreased renal function - dapagliflozin: Adverse drug reactions related to increased creatinine were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). In the 13-study safety pool, this grouping of reactions was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR ≥60 mL/min/1.73 m2) this grouping of reactions were reported in 1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. These reactions were more common in patients with baseline eGFR ≥30 and <60 mL/min/1.73 m2 (18.5% dapagliflozin 10 mg vs 9.3% placebo).
Further evaluation of patients who had renal-related adverse events showed that most had serum creatinine changes of ≤44 micromoles/L (≤0.5 mg/dL) from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment.
In the DAPA-CKD study, eGFR decreased over time in both the dapagliflozin group and the placebo group. The initial (day 14) decrease in mean eGFR was 4.0 mL/min/1.73 m2 in the dapagliflozin group and 0.8 mL/min/1.73 m2 in the placebo group. At 28 months, change from baseline in eGFR was 7.4 mL/min/1.73 m2 in the dapagliflozin group and 8.6 mL/min/1.73 m2 in the placebo group.
Pharmacokinetics: The pharmacokinetics of the individual mono-components were generally similar in healthy subjects and in patients with type 2 diabetes mellitus.
Dapagliflozin/sitagliptin combination: Bioequivalence has been confirmed between the SIDAPVIA 10 mg/100 mg tablet and the individual dapagliflozin 10 mg and sitagliptin 100 mg tablets after single dose co-administration in the fasted state in healthy subjects.
Geometric mean ratios and corresponding 90% CIs for all primary PK parameters of dapagliflozin and sitagliptin were contained well within the bioequivalence acceptance limit of 80-125%, demonstrating that bioequivalence was achieved between the SIDAPVIA 10 mg/100 mg tablet and dapagliflozin 10 mg + sitagliptin 100 mg co-administered individual tablets.
Between-subject variability (gCV%) in PK exposures was up to approximately 30% and 25% for dapagliflozin Cmax and AUCs, respectively, and up to approximately 32% and 20% for sitagliptin Cmax and AUCs, respectively, and similar between treatments.
Absorption: Dapagliflozin: Dapagliflozin is rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (Cmax) are usually attained within 2 hours after administration in the fasted state. The Cmax 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 Cmax by up to 50% and prolonged Tmax 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 (This information is based on studies related to the innovator of sitagliptin): Following 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, mean plasma AUC of sitagliptin was 8.52 μM·hr, Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87%. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, it may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
Distribution: Dapagliflozin: Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in various disease states (e.g., renal or hepatic impairment).
Sitagliptin (This information is based on studies related to the innovator of 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-carbon bond, thereby conferring stability against glucosidase enzymes. The mean plasma terminal half-life (t½) 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 (This information is based on studies related to the innovator of Sitagliptin): 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 DPP4 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.
In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
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 (This information is based on studies related to the innovator of sitagliptin): Following administration of an oral [14C] sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week of dosing. The apparent terminal t½ following a 100-mg oral dose of sitagliptin was approximately 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The 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-gp, which may also be involved in mediating the renal elimination of sitagliptin. However, ciclosporin, a P-gp inhibitor, did not reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2 transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50=160 μM) or P-gp (up to 250 μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor of P-gp.
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 (This information is based on studies related to the innovator of 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 Cmax 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 Cmax and AUC of dapagliflozin were up to 40% and 67% higher than matched healthy controls, respectively. No dose adjustment is required for patients with severe hepatic impairment.
Sitagliptin (This information is based on studies related to the innovator of 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 (This information is based on studies related to the innovator of 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: Pharmacokinetics in the paediatric population have not been studied.
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 (This information is based on studies related to the innovator of 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 (This information is based on studies related to the innovator of 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 (This information is based on studies related to the innovator of 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.
Dapagliflozin: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility. Dapagliflozin did not induce tumours in either mice or rats at any of the doses evaluated in two-year carcinogenicity studies.
Reproductive and development toxicity: 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 ≥15x 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 1415x and 137x, 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 ≥29x 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 (1,441x the MRHD). Doses ≥150 mg/kg/day (≥2,344x 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.
Sitagliptin (This information is based on studies related to the innovator of Sitagliptin): Carcinogenesis, Mutagenesis, Impairment of Fertility: 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 tumours 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 tumours 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 1,000 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, non-dose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
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