Qtern Mechanism of Action

Pharmacology: Mechanism of Action: QTERN combines saxagliptin and dapagliflozin with distinct and complementary mechanisms of action to improve glycaemic control. Saxagliptin, through the selective inhibition of dipeptidyl peptidase-4 (DPP-4), enhances glucose-mediated insulin secretion (incretin effect). Dapagliflozin, a selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), inhibits renal glucose reabsorption independently of insulin. Actions of both drugs are regulated by the plasma glucose level. The combination of both agents delivers clinically meaningful reductions in HbA_1c for improved glycaemic control in patients with T2DM. While saxagliptin has a neutral effect on weight, urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric and weight loss.
Saxagliptin: Saxagliptin is a member of a class of oral anti-hyperglycaemic agents called DPP-4 inhibitors. Saxagliptin is a reversible, competitive, DPP-4 inhibitor with nanomolar potency. Saxagliptin demonstrates selectivity for DPP-4 versus other DPP enzymes, with greater than 75-fold selectivity over DPP-8 and DPP-9. Saxagliptin has extended binding to the DPP-4 active site, prolonging its inhibition of DPP-4. Saxagliptin exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Concentrations of these active intact incretin hormones are increased by saxagliptin, thereby increasing and prolonging the actions of these hormones.
Dapagliflozin: Dapagliflozin is a reversible competitive inhibitor of sodium glucose co-transporter 2 (SGLT2) with nanomolar potency that improves glycaemic control in patients with type 2 diabetes mellitus and provides cardio renal benefits.
Inhibition of SGLT2 by dapagliflozin reduces reabsorption of glucose from the glomerular filtratein 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 is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure. Secondary effects of SGLT2 inhibition with dapagliflozin also include a modest reduction in blood pressure, reduction in body weight, and an increase in haematocrit.
The cardio-renal benefits of dapagliflozin are not solely dependent on the blood glucose lowering effect and not limited to patients with diabetes. In addition to the osmotic diuretic and related hemodynamic actions of SGLT2 inhibition, potential secondary effects on myocardial metabolism, ion channels, fibrosis, adipokines and uric acid may be mechanisms underlying the cardio-renal beneficial effects of dapagliflozin. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. 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 glucose, dapagliflozin has a low propensity to cause hypoglycaemia. 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 the weight reduction was 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.
SGLT2 is selectively expressed in the kidney. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is approximately 1000-3000 times more selective for SGLT2 vs. SGLT1, the major transporter in the gut responsible for glucose absorption.
Pharmacodynamic effects: Saxagliptin: In patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour 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 glucose-dependent beta-cell responsiveness, which resulted in higher insulin and C peptide concentrations. The rise in insulin and the decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
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 dose 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 18.3 to 48.3 μmol/L.
Clinical Trials: Glycaemic control: Concomitant therapy of saxagliptin 5 mg and dapagliflozin 10 mg in comparison to glimepiride in patients inadequately controlled on metformin: A 52-week randomised, double-blind, active-controlled, parallel-group study with a blinded 104-week extension compared orally once daily saxagliptin 5 mg and dapagliflozin 10 mg co-administered in combination with metformin to once daily glimepiride (a sulphonylurea) up-titrated1-6 mg plus placebo with metformin (≥1500 mg per day) in T2DM patients with inadequate glycaemic control (HbA1c ≥7.5% and ≤10.5%) on metformin alone. Patients on glimepiride/placebo dose were up-titrated starting at 1 mg per day over 12 weeks to optimal glycaemic effect (FPG <6.1 mmol/L) or the highest tolerable dose during the first 12 weeks. Thereafter, glimepiride/placebo dose were kept constant, except for down-titration to prevent hypoglycaemia.
Saxagliptin 5 mg and dapagliflozin 10 mg plus metformin had a statistically greater mean reduction in HbA1c from baseline at Week 52, compared with glimepiride plus metformin, demonstrating superiority (Table 1).
Fewer treatment intensification events occurred in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group (n=3) compared with the glimepiride plus metformin group (n=19). A total of 3 subjects (1.3%) in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group and 18 subjects (8.3%) in the glimepiride plus metformin group were rescued during the treatment period. The most common rescue treatment was insulin (2 subjects [0.9%] in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group and 11 subjects [5.1%] in the glimepiride plus metformin group). (See Table 1.)

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Proportion of patients achieving HbA1c <7%: The proportion of patients achieving HbA1c <7.0% at Week 52 was higher in the saxagliptin 5 mgand dapagliflozin 10 mg plus metformin group (44.3% 95% CI [37.45, 51.32]) compared to the glimepiride plus metformin group (34.3% 95% CI [27.87, 41.33] p = 0.044).
Systolic blood pressure: The decrease in systolic blood pressure at Week 52 in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group (-2.6 mmHg 95% CI [-4.4, -0.8]) was greater than in the glimepiride plus metformin group (1.0 mmHg 95% CI [-0.9, 2.9]). The difference in mean systolic blood pressure between treatment groups was-3.6 mmHg (95% CI [-6.3, -1.0] p = 0.007).
Body weight: Treatment with saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group resulted insignificant difference in mean body weight change at Week 52 compared to glimepiride plus metformin. The adjusted mean change from baseline was -3.11 kg (95% CI [-3.65, -2.57]) for the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group, and 0.95 kg (95% CI [0.38, 1.51]) for the glimepiride plus metformin group. The difference in mean body weight between treatment groups was -4.06 kg (95% CI [-4.84, -3.28] p <0.001).
Concomitant therapy of saxagliptin 5 mg and dapagliflozin 10 mg in comparison to insulin glargine in patients inadequately controlled on metformin with or without a sulfonylurea: A 24-week randomised, open-label, active-controlled, parallel-group study with a 28-week extension compared orally once daily saxagliptin 5 mg and dapagliflozin 10 mg co-administered with metformin with or without a sulfonylurea to titrated subcutaneous insulin glargine coadministered with metformin with or without a sulfonylurea in T2DM patients with inadequate glycaemic control (HbA1c ≥8.0% and ≤12.0%).
Saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without a sulfonylurea group met the predefined criteria for non-inferiority in HbA1c reduction from baseline compared to insulin glargine plus metformin with or without a sulfonylurea group after 24 weeks of open-label treatment. (See Table 2.)

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Hypoglycaemia events with glucose ≤3.9 mmol/LA substantially lower proportion of patients in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without a sulfonylurea group (11.4% of N=324) experienced at least one event of hypoglycaemia (glucose ≤3.9 mmol/L with symptoms) at Week 24 than the titrated insulin glargine plus metformin with or without a sulfonylurea group (24.5% of N=319). There were 57 events of hypoglycaemia in 26 patients with SU and 16 events in 11 patients without sulfonylurea in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group; there were 233 events of hypoglycaemia in 52 patients with sulfonylurea and 65 events in 26 patients without sulfonylurea in the insulin glargine plus metformin group.
Continuous glucose monitoring: After 2 weeks of open-label treatment, patients in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without a sulfonylurea group demonstrated a mean decrease from baseline in 24-hour mean glucose as measured by 24-hour continuous glucose monitoring (CGM) of -2.69 mmol/L (95% CI [-2.97, -2.42]) compared to the insulin glargine plus metformin with or without a sulfonylurea group -1.58 mmol/L (95% CI [-1.86, -1.31]). The difference in the least squared mean change between the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without a sulfonylurea group and insulin glargine plus metformin with or without a sulfonylurea group was -1.11 mmol/L (95% CI [-1.50, -0.72]) p < 0.0001).
Body weight: Treatment with saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without a sulfonylurea group resulted in significant difference in body weight change at Week 24, mean change from baseline -1.50 kg (95% CI [-1.89, -1.11]) versus 2.14 kg (95% CI [1.75, 2.54]) in the insulin glargine plus metformin with or without a sulfonylurea group. The difference in mean body weight between treatment groups was -3.64 kg (95% CI [-4.20, -3.09] p < 0.001).
Proportion of patients achieving HbA_1c < 7%: The adjusted percent (95% CI) of patients achieving a therapeutic glycaemic response (HbA_1c <7%) at Week 24 was 33.2% (28.0, 38.8) in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without sulfonylurea group and 33.5% (28.3, 39.3) in the insulin glargine plus metformin with or without sulfonylurea group (difference -0.4% 95% CI [-7.42, 6.54]). Noninferiority of saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without sulfonylurea compared with the insulin glargine plus metformin with or without sulfonylurea group was demonstrated (non-inferiority defined by lower bound of 95% CI > 10%).
Add-on therapy with dapagliflozin in patients inadequately controlled on saxagliptin plus metformin: In a 24-week randomised, double-blind, placebo-controlled study with the sequential addition of 10 mg dapagliflozin to 5 mg saxagliptin and metformin was compared to the addition of placebo to 5 mg saxagliptin and metformin in patients with inadequate glycaemic control (HbA_1c ≥7% and ≤10.5% at Week-2). Subject disposition for this study is presented in Figure 1.
Mean duration of diabetes was 7.6 years at randomised baseline. Patients who completed the initial 24-week study period were eligible to enter a controlled 28-week long-term study extension (52 weeks). (See Figure 1.)

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The safety profile of dapagliflozin added to saxagliptin plus metformin in the long-term treatment period was consistent with that previously observed in the clinical trial experience for the concomitant therapy study and that observed in the 24-week treatment period in this study.
The group with dapagliflozin sequentially added to saxagliptin and metformin achieved statistically significantly (p-value <0.0001) greater reductions in HbA_1c versus the group with placebo sequentially added to saxagliptin plus metformin group at 24 weeks (see Table 1). The effect in HbA_1c observed at Week 24 was sustained at Week 52.
Add-on therapy with saxagliptin in patients inadequately controlled on dapagliflozin plus metformin In a 24-week randomised, double-blind, placebo-controlled study with the sequential addition of saxagliptin 5 mg to dapagliflozin 10 mg and metformin was compared to the addition of placebo to dapagliflozin 10 mg (SGLT2 inhibitor) and metformin in subjects with T2DM with inadequate glycaemic control (HbA_1c ≥7% and ≤10.5%) on metformin and dapagliflozin. Subject disposition for this study is presented in Figure 2.
Mean duration of diabetes was 7.7 years at randomised baseline. Patients who completed the initial 24-week study period were eligible to enter a controlled 28-week long-term study extension (52 weeks). (See Figure 2.)

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The safety profile of saxagliptin added to dapagliflozin plus metformin in the long-term treatment period was consistent with that previously observed in the clinical trial experience for the concomitant therapy study and that observed in the 24-week treatment period in this study.
The group with saxagliptin sequentially added to dapagliflozin and metformin achieved statistically significant (p-value <0.0001) greater reductions in HbA_1c versus the group with placebo sequentially added to dapagliflozin plus metformin group at 24 weeks (see Table 1). The effect in HbA_1c observed at Week 24 was sustained at Week 52. (See Tables 3 and 4.)

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Body weight: In the concomitant therapy study, the adjusted mean change from baseline in body weight at Week-24 (excluding data after rescue) was -2.05 kg (-2.27%) in the saxagliptin 5 mg plus dapagliflozin 10 mg plus metformin group and -2.39 kg (-2.67%) in the dapagliflozin 10 mg plus metformin group, while the saxagliptin 5 mg plus metformin group had no change (0.03%). In the saxagliptin add-on study, both treatment groups had similar small mean changes in body weight at Week-24 from baseline: -0.53 kg (-0.50%) for the saxagliptin plus dapagliflozin plus metformin group and -0.51 kg (-0.55%) for the placebo plus dapagliflozin plus metformin group. In the dapagliflozin add-on study, the adjusted changes from baseline at Week 24 in body weight were -1.91 kg (-2.23%) in the dapagliflozin plus saxagliptin plus metformin group and -0.41 kg (-0.47%) in the placebo plus saxagliptin plus metformin group.
Blood pressure: Consistent with its mild diuretic effect, the pre-specified analysis of dapagliflozin-containing treatments in the three studies were associated with decreases from baseline in systolic and diastolic blood pressure. Treatment with saxagliptin/dapagliflozin combination resulted in change from baseline for systolic blood pressure ranging from -1.3 to -2.2 mmHg and for diastolic blood pressure ranging from -0.5 to -1.2 mmHg. The modest lowering effects on BP were consistent over time and a similar number of subjects had systolic BP <130 mmHg or diastolic BP <80 mmHg at Week-24 across the treatment groups.
Supportive Studies: Moderate renal impairment CKD 3A (eGFR ≥45 to < 60 m:/min/1.73 m²): Dapagliflozin: 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 (Table 5). (See Table 5.)

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At Week 24, treatment with dapagliflozin demonstrated reductions in fasting plasma glucose (FPG) -1.19 mmol/L compared to -0.27 mmol/L for placebo (p ≤ 0.001), and reductions in seated systolic blood pressure (SBP) -4.8 mmHg compared to -1.7 mmHg for placebo (p < 0.05).
The safety profile of dapagliflozin in the study was consistent with that in the general population of patients with type 2 diabetes. Mean eGFR decreased initially during the treatment period in the dapagliflozin group and subsequently remained stable during the 24-week treatment period (FORXIGA: -3.39 mL/min/1.73 m² and placebo: -0.90 mL/min/1.73 m²). At 3 weeks after termination of FORXIGA, the mean change from baseline in eGFR in the dapagliflozin group was similar to the mean change in the placebo group (FORXIGA: 0.57 mL/min/1.73 m² and placebo: - 0.04 mL/min/1.73 m²).
For further information on clinical trial experience with saxagliptin and dapagliflozin, refer to the appropriate individual Product Information document.
Pharmacokinetics: Saxagliptin/dapagliflozin combination: Bioequivalence has been confirmed between the QTERN 5 mg/10 mg tablet and the individual saxagliptin 5 mg and dapagliflozin 10 mg tablets after single dose administration in the fasted state in healthy volunteers.
Administration of QTERN with a high-fat meal decreases dapagliflozin C_max by up to 47% and prolongs T_max by approximately 2 hours, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful. There was no food effect observed for saxagliptin. QTERN can be administered with or without food.
Saxagliptin: The pharmacokinetics of saxagliptin have been extensively characterised in healthy subjects and patients with type 2 diabetes. Saxagliptin was rapidly absorbed after oral administration, with maximum saxagliptin plasma concentrations (C_max) usually attained within two hours after administration in the fasted state. The C_max and AUC values increased proportionally to the increment in the saxagliptin dose. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC_(INF) values for saxagliptin and its major metabolite were 78 ng·h/mL and 214 ng·h/mL, respectively. The corresponding plasma C_max values were 24 ng/mL and 47 ng/mL, respectively. The intra-subject coefficients of variation for saxagliptin C_max and AUC were less than 12%.
Following a single oral dose of 5 mg saxagliptin to healthy subjects, the mean plasma terminal half-life (t_½) for saxagliptin was 2.5 hours and the mean t_½ value for plasma DPP-4 inhibition was 26.9 hours. The inhibition of plasma DPP-4 activity by saxagliptin for at least 24 hours after oral administration of saxagliptin is due to high potency, high affinity, and extended binding to the active site. No appreciable accumulation was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg.
Results from population-based exposure modelling suggest that the pharmacokinetics of saxagliptin and its major metabolite were similar in healthy subjects and in patients with type 2 diabetes.
Absorption: Saxagliptin: The amount of saxagliptin absorbed following an oral dose is at least 75%. The absolute oral bioavailability of saxagliptin is approximately 50% (90% CI of 48-53%). Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects. Administration with a high-fat meal resulted in no change in saxagliptin C_max and a 27% increase in AUC compared with the fasted state. The time for saxagliptin to reach C_max (T_max) was increased by approximately 0.5 hours with food compared with the fasted state. These changes were not considered to be clinically meaningful.
Dapagliflozin: Dapagliflozin was rapidly and well absorbed after oral administration and can be administered with or without food. Maximum dapagliflozin plasma concentrations (C_max) were usually attained within 2 hours after administration in the fasted state. The C_max and AUC values increased proportional to the increment in dapagliflozin dose. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food had relatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. Administration with a high-fat meal decreased dapagliflozin C_max by up to 50% and prolonged T_max by approximately 1 hour, but did not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful.
Distribution: Saxagliptin: The in vitro protein binding of saxagliptin and its major metabolite in human serum is below measurable levels. Thus, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.
Dapagliflozin: Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in various disease states (e.g., renal or hepatic impairment).
Metabolism: Saxagliptin: The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a selective, reversible, competitive DPP-4 inhibitor, half as potent as saxagliptin.
Dapagliflozin: Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide. Dapagliflozin 3-O-glucuronide, with a molar plasma AUC 52% higher than that of dapagliflozin itself at the clinical dose, is an inactive metabolite and does 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 was a minor clearance pathway in humans.
Excretion: Saxagliptin: Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of ¹⁴C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. For the major metabolite, renal clearance values were comparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivity was recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract.
Dapagliflozin: Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of which less than 2% is unchanged dapagliflozin. After oral administration of 50 mg [¹⁴C] dapagliflozin dose, 96% was recovered, 75% in urine and 21% in faeces. In faeces, approximately 15% of the dose was excreted as parent drug. The mean plasma terminal half-life (t_½) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects.
Pharmacokinetics of the major metabolite: Saxagliptin: The C_max and AUC values for the major metabolite of saxagliptin increased proportionally to the increment in the saxagliptin dose. Following single oral doses of 2.5 mg to 400 mg saxagliptin in the fed or fasted states, the mean AUC values for the major metabolite ranged from 2- and 7-times higher than the parent saxagliptin exposures on a molar basis. Following a single oral dose of 5 mg saxagliptin in the fasted state, the mean terminal half-life (t_½) value for the major metabolite was 3.1 hours and no appreciable accumulation was observed upon repeated once-daily dosing at any dose.
Special Populations: Renal impairment: Saxagliptin/dapagliflozin combination: Use of QTERN is not recommended in patients with eGFR<45 ml/min/1.73 m² or end-stage renal disease (see Precautions).
Saxagliptin: A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The study included patients with renal impairment 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 End Stage Renal Disease (ESRD) on haemodialysis. Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault formula: (See equation.)

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The degree of renal impairment did not affect the C_max of saxagliptin or its major metabolite. In subjects with mild renal impairment, the AUC values of saxagliptin and its major metabolite were 1.2- and 1.7-fold higher, respectively, than AUC values in subjects with normal renal function. Increases of this magnitude are not clinically relevant, therefore dosage adjustment in these patients with mild renal impairment with CrCL ≤50 mL/min (approximately corresponding to eGFR <45 mL/min/1.73 m², following post-hoc re-analysis) is not recommended. In subjects with moderate or severe renal impairment or in subjects with ESRD on haemodialysis, the AUC values of saxagliptin and its major metabolite were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal function. Use of saxagliptin in patients with ESRD requiring haemodialysis is not recommended.
Dapagliflozin: Dapagliflozin should not be used in patients with eGFR persistently <45 mL/min/1.73 m². At steady-state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes 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 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-h 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.
Hepatic impairment: Saxagliptin/dapagliflozin combination: See Precautions.
Saxagliptin: There were no clinically meaningful differences in pharmacokinetics for subjects with mild, moderate, or severe hepatic impairment; therefore, no dosage adjustment for saxagliptin is recommended for patients with hepatic impairment. In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean C_max and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin. The corresponding C_max and AUC of the major metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful.
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 hepatic impairment groups or 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.
Body Mass Index: Saxagliptin: No dosage adjustment is recommended based on body mass index (BMI). BMI was not identified as a significant covariate on the apparent clearance of saxagliptin or its major metabolite in an exposure modelling analysis.
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 patients with 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 patients with type 2 diabetes mellitus patients with low body weight (<50 kg) is recommended.
Elderly: Saxagliptin/dapagliflozin combination: See Precautions.
Saxagliptin: Elderly subjects (65-80 years) had 23% and 59% higher geometric mean C_max and geometric mean AUC values, respectively, for parent saxagliptin than young subjects (18-40 years). Differences in major metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in parent saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the major metabolite in young and elderly subjects is likely to be due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as a significant covariate on the apparent clearance of saxagliptin and its major metabolite in an exposure modelling analysis.
Dapagliflozin: 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%]. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients >70 years old.
Paediatric and adolescent: Pharmacokinetics in the paediatric population have not been studied.
Gender: Saxagliptin/dapagliflozin combination: QTERN may be used regardless of gender.
Saxagliptin: There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the major metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as a significant covariate on the apparent clearance of saxagliptin and its major metabolite in an exposure modelling analysis.
Dapagliflozin: Gender was evaluated as a covariate in a population pharmacokinetic model using data from healthy subject and patient studies. The mean dapagliflozin AUC_ss in females (n=619) was estimated to be 22% higher than in males (n=634) (90% CI; 117,124).
Race: Saxagliptin/dapagliflozin combination: QTERN may be used regardless of race.
Saxagliptin: An exposure modelling analysis compared the pharmacokinetics of saxagliptin and its major metabolite in 309 white subjects with 105 non-white subjects (consisting of 6 racial groups). No significant difference in the pharmacokinetics of saxagliptin and its major metabolite were detected between these two populations.
Dapagliflozin: Race (White, Black [African descent], 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 (African descent) subjects (n=43) had 4.9% lower estimated mean dapagliflozin systemic exposures [90% CI range; 7.7% lower, 3.7% lower].