Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering drugs, ATC code: A10BD24.

Mechanism of action
Steglujan combines two antihyperglycaemic agents with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: ertugliflozin, a SGLT2 inhibitor, and sitagliptin phosphate, a DPP-4 inhibitor.

Ertugliflozin
SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Ertugliflozin is a potent, selective, and reversible inhibitor of SGLT2.
By inhibiting SGLT2, ertugliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Sitagliptin
Sitagliptin is a member of a class of oral antihyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) 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 DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyses the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases 
glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower haemoglobin A1c (HbA1c) and lower fasting and post-prandial 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 and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.

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.

Pharmacodynamic effects

Ertugliflozin
Urinary glucose excretion and urinary volume
Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following single- and multiple-dose administration of ertugliflozin. Dose-response modelling indicates that ertugliflozin 5 mg and 15 mg result in near maximal urinary glucose excretion (UGE) in patients with type 2 diabetes mellitus, providing 87% and 96% of maximal inhibition, respectively.

Clinical efficacy and safety

Ertugliflozin in combination with sitagliptin
The efficacy and safety of ertugliflozin in combination with sitagliptin have been studied in 3 multi- centre, randomised, double-blind, placebo- and active comparator-controlled, Phase 3 clinical studies involving 1,985 patients with type 2 diabetes. Across the 3 studies, the racial distribution ranged from 72.9% to 90.4% White, 0.0% to 20.3% Asian, 1.9% to 4.5% Black and 4.8% to 5.4% Other. Hispanic or Latino patients comprised 15.6% to 36.1% of the population. The mean age of the patients across these 3 studies ranged from 55.1 to 59.1 years (range 21 years to 85 years). Across the 3 studies, 16.2% to 29.9% of patients were ≥ 65 years of age and 2.3% to 2.8% were ≥ 75 years of age.

Factorial study with ertugliflozin and sitagliptin as add-on combination therapy with metformin A total of 1,233 patients with type 2 diabetes participated in a randomised, double-blind, multi-centre, 26-week, active-controlled study to evaluate the efficacy and safety of ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg compared to the individual components. Patients with type 2 diabetes inadequately controlled on metformin monotherapy (≥ 1,500 mg/day) were randomised to one of five active-treatment arms: ertugliflozin 5 mg or 15 mg, sitagliptin 100 mg, or sitagliptin 100 mg in combination with 5 mg or 15 mg ertugliflozin administered once daily in addition to continuation of background metformin therapy (see Table 2).


Table 2: Results at Week 26 from a factorial study with ertugliflozin and sitagliptin as add-on combination therapy with metformin compared to individual components alone* 
Ertugliflozin    Ertugliflozin         Sitagliptin      Ertugliflozin 5 mg +          Ertugliflozin 15 mg 5 mg             15 mg               100 mg           Sitagliptin 100 mg           + Sitagliptin 100 mg 

HbA1c (%)                                 N = 250            N = 248           N = 247                 N = 243                     N = 244 Baseline (mean)                            8.6                8.6               8.5                      8.6                         8.6 
Change from baseline (LS mean†)            -1.0               -1.1              -1.1                    -1.5                        -1.5 
Difference from
Sitagliptin                                                                                     -0.4‡ (-0.6, -0.3)          -0.5‡ (-0.6, -0.3) Ertugliflozin 5 mg                                                                              -0.5‡ (-0.6, -0.3) Ertugliflozin 15 mg                                                                                                         -0.4‡ (-0.6, -0.3) (LS mean†, 95% CI)


Patients [N (%)] with HbA1c < 7%         66 (26.4)           79 (31.9)        81 (32.8)              127 § (52.3)                120 § (49.2) 
Body weight (kg)                          N = 250            N = 248           N = 247                 N = 243                     N = 244 
Baseline (mean)                            88.6               88.0              89.8                    89.5                        87.5 
Change from baseline (LS mean†)            -2.7               -3.7              -0.7                    -2.5                        -2.9 
Difference from Sitagliptin                                                                       -1.8‡ (-2.5, -1.2)          -2.3‡ (-2.9, -1.6) (LS mean†, 95% CI)
* N includes all randomised, treated patients who had at least one measurement of the outcome variable.
†
Least squares means adjusted for time, baseline eGFR and the interaction of time by treatment.
‡ p< 0.001 compared to control group.
§ p< 0.001 compared to corresponding dose of ertugliflozin or sitagliptin (based on adjusted odds ratio comparisons from a logistic regression model using multiple imputation for missing data values).


Ertugliflozin as add-on combination therapy with metformin and sitagliptin A total of 463 patients, with type 2 diabetes inadequately controlled on metformin (≥ 1,500 mg/day) and sitagliptin 100 mg once daily participated in a randomised, double-blind, multi-centre, 26-week, placebo-controlled study to evaluate the efficacy and safety of ertugliflozin. Patients were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo administered once daily in addition to continuation of background metformin and sitagliptin therapy (see Table 3).

Table 3: Results at Week 26 from an add-on study of ertugliflozin in combination with metformin and sitagliptin*

Ertugliflozin 5 mg       Ertugliflozin 15 mg             Placebo

HbA1c (%)                                                      N = 156                   N = 153                 N = 153 Baseline (mean)                                                  8.1                       8.0                     8.0 Change from baseline (LS mean†)                                 -0.8                       -0.9                    -0.1 Difference from placebo (LS mean†, 95% CI)              -0.7‡ (-0.9, -0.5)         -0.8‡ (-0.9, -0.6) §
Patients [N (%)] with HbA1c < 7%                              50 (32.1)                 61 (39.9)§               26 (17.0) 
Body Weight (kg)                                               N = 156                   N = 153                 N = 153 Baseline (mean)                                                 87.6                       86.6                    86.5 Change from baseline (LS mean†)                                 -3.3                       -3.0                    -1.3 Difference from placebo (LS mean†, 95% CI)              -2.0‡ (-2.6, -1.4)         -1.7‡ (-2.3, -1.1) * N includes all randomised, treated patients who had at least one measurement of the outcome variable.
†  Least squares means adjusted for time, prior antihyperglycaemic medication, baseline eGFR, and the interaction of time by treatment.
‡ p< 0.001 compared to placebo.
§ p< 0.001 compared to placebo (based on adjusted odds ratio comparisons from a logistic regression model using multiple imputation for missing data values).


Combination therapy of ertugliflozin and sitagliptin
A total of 291 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a randomised, double-blind, multi-centre, placebo-controlled 26-week study to evaluate the efficacy and safety of ertugliflozin in combination with sitagliptin. These patients, who were not receiving any background antihyperglycaemic treatment, were randomised to ertugliflozin 5 mg or ertugliflozin 15 mg in combination with sitagliptin (100 mg) or to placebo, once daily (see Table 4).

Table 4: Results at Week-26 from a combination therapy study of ertugliflozin and sitagliptin* 
Ertugliflozin 5 mg         Ertugliflozin           Placebo
+ Sitagliptin               15 mg
+ Sitagliptin

HbA1c (%)                                                      N = 98                 N = 96               N = 96 Baseline (mean)                                               8.9                     9.0                  9.0 Change from baseline (LS mean†)                               -1.6                   -1.7                 -0.4 Difference from placebo (LS mean† and 95%              -1.2‡ (-1.5, -0.8)      -1.2‡ (-1.6, -0.9) CI)
Patients [N (%)] with HbA1c < 7%                            35 (35.7)§              30 (31.3)§             8 (8.3) Body Weight (kg)                                               N = 98                 N = 96               N = 97 Baseline (mean)                                               90.8                   91.3                 95.0 Change from baseline (LS mean†)                               -2.9                   -3.0                 -0.9 Difference from placebo (LS mean†, 95% CI)             -2.0‡ (-3.0, -1.0)      -2.1‡ (-3.1, -1.1) * N includes all patients who received at least one dose of study medication and had at least one measurement of the outcome variable.
† Least squares means adjusted for time, and the interaction of time by treatment.
‡ p< 0.001 compared to placebo.
§ p< 0.001 compared to placebo (based on adjusted odds ratio comparisons from a logistic regression model using multiple imputation for missing data values).


Fasting plasma glucose
In three placebo-controlled studies, ertugliflozin resulted in statistically significant reductions in FPG.
For ertugliflozin 5 mg and 15 mg, respectively, the placebo-corrected reductions in FPG were 1.92 and 2.44 mmol/L as monotherapy, 1.48 and 2.12 mmol/L as add-on to metformin, and 1.40 and
1.74 mmol/L as add-on to metformin and sitagliptin.

The combination of ertugliflozin and sitagliptin resulted in significantly greater reductions in FPG compared to sitagliptin or ertugliflozin alone or placebo. The combination of ertugliflozin 5 or 15 mg and sitagliptin resulted in incremental FPG reductions of 0.46 to 0.65 mmol/L compared to the ertugliflozin alone or 1.02 to 1.28 mmol/L compared to sitagliptin alone. The placebo-corrected reductions of ertugliflozin 5 or 15 mg in combination with sitagliptin were 2.16 and 2.56 mmol/L.

Efficacy in patients with baseline HbA1c ≥ 10%
In the study of patients inadequately controlled on metformin with baseline HbA1c from 7.5-11.0%, among the subgroup of patients with a baseline HbA1c ≥ 10%, the combination of ertugliflozin 5 mg or 15 mg with sitagliptin resulted in reductions of HbA1c of 2.35% and 2.66%, respectively, compared to 2.10%, 1.30%, and 1.82% for ertugliflozin 5 mg, ertugliflozin 15 mg, and sitagliptin alone, respectively.

Post-prandial glucose
When used in monotherapy, ertugliflozin 5 and 15 mg resulted in statistically significant placebo- corrected reductions in 2-hour post-prandial glucose (PPG) of 3.83 and 3.74 mmol/L.

The combination of ertugliflozin 5 or 15 mg with sitagliptin resulted in statistically significant placebo-corrected reductions in 2-hour PPG of 3.46 and 3.87 mmol/L.

Blood pressure
After 26-weeks of treatment, the combination of ertugliflozin 5 mg or 15 mg and sitagliptin 100 mg resulted in statistically significant reductions in systolic blood pressure (SBP) compared to sitagliptin alone (-2.8 and -3.0 mmHg for E5/S100 and E15/S100 respectively) or placebo (-4.4 and -6.4 mmHg for E5/S100 and E15/S100, respectively). Additionally, when added on to background metformin and sitagliptin therapy, ertugliflozin 5 mg and 15 mg resulted in statistically significant placebo subtracted reductions in SBP of 2.9 and 3.9 mmHg, respectively.

Subgroup analysis
In patients with type 2 diabetes treated with ertugliflozin in combination with sitagliptin, the improvement in HbA1c was similar across subgroups defined by age, sex, and race, and duration of type 2 diabetes mellitus.

Sitagliptin cardiovascular outcomes study (TECOS)
The TECOS was a randomised study in 14,671 patients in the intention-to-treat population with an HbA1c of ≥ 6.5 to 8.0% with established CV disease who received sitagliptin (7,332) 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2) or placebo (7,339) added to usual care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR < 30 mL/min/1.73 m2 were not to be enrolled in the study. The study population included 2,004 patients ≥ 75 years of age and 3,324 patients with renal impairment
(eGFR < 60 mL/min/1.73 m2).

Over the course of the study, the overall estimated mean (SD) difference in HbA1c between the sitagliptin and placebo groups was 0.29% (0.01), 95% CI (-0.32, -0.27); p< 0.001. The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for unstable angina. Secondary cardiovascular endpoints included the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke; first occurrence of the individual components of the primary composite; all-cause mortality; and hospital admissions for congestive heart failure.

After a median follow up of 3 years, 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 (see Table 5).


Table 5: Rates of composite cardiovascular outcomes and key secondary outcomes 
Sitagliptin 100 mg               Placebo


Incidenc                    Incidence e rate                     rate per per 100                       100 patient-                     patient-      Hazard Ratio
N (%)        years*        N (%)          years*         (95% CI)         p-value† Analysis in the Intention-to-Treat Population

Number of patients
7,332                        7,339

Primary Composite Endpoint
(Cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for                                     851 unstable angina)                     839 (11.4)       4.1         (11.6)           4.2     0.98 (0.89–1.08)      < 0.001 

Secondary Composite Endpoint
(Cardiovascular death, non-fatal myocardial infarction, or non-                                     746 fatal stroke)                        745 (10.2)       3.6         (10.2)           3.6     0.99 (0.89–1.10)      < 0.001 Secondary Outcome

Cardiovascular death
380 (5.2)        1.7       366 (5.0)          1.7      1.03 (0.89-1.19)      0.711 All myocardial infarction (fatal and non-fatal)                       300 (4.1)        1.4       316 (4.3)          1.5     0.95 (0.81–1.11)       0.487 
All stroke (fatal and non-fatal)
178 (2.4)        0.8       183 (2.5)          0.9     0.97 (0.79–1.19)       0.760 
Hospitalisation for unstable angina                               116 (1.6)        0.5       129 (1.8)          0.6     0.90 (0.70–1.16)       0.419 
Death from any cause                 547 (7.5)        2.5       537 (7.3)          2.5     1.01 (0.90–1.14)       0.875 
Hospitalisation for heart failure‡
228 (3.1)        1.1       229 (3.1)          1.1     1.00 (0.83–1.20)       0.983 *Incidence rate per 100 patient-years is calculated as 100 × (total number of patients with ≥ 1 event during eligible exposure period per total patient-years of follow-up).
†
Based on a Cox model stratified by region. For composite endpoints, the p-values correspond to a test of non-inferiority seeking to show that the hazard ratio is less than 1.3. For all other endpoints, the p-values correspond to a test of differences in hazard rates.
‡The analysis of hospitalisation for heart failure was adjusted for a history of heart failure at baseline.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

Steglujan
Steglujan has been shown to be bioequivalent to coadministration of corresponding doses of ertugliflozin and sitagliptin tablets.

The effects of a high-fat meal on the pharmacokinetics of ertugliflozin and sitagliptin when administered as Steglujan tablets are comparable to those reported for the individual tablets.
Administration of Steglujan with food decreased ertugliflozin C max by 29% and had no meaningful effect on ertugliflozin AUC inf, or on sitagliptin AUCinf and Cmax.

Ertugliflozin

General introduction
The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes.
The steady state mean plasma AUC and C max were 398 ng∙hr/mL and 81 ng/mL, respectively, with 5 mg ertugliflozin once daily treatment, and 1,193 ng∙hr/mL and 268 ng/mL, respectively, with 15 mg 
ertugliflozin once daily treatment. Steady-state is reached after 4 to 6 days of once-daily dosing with ertugliflozin. Ertugliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up to 10-40% following multiple dosing.

Absorption
Following single-dose oral administration of 5 mg and 15 mg of ertugliflozin, peak plasma concentrations (median Tmax) of ertugliflozin occur at 1 hour post-dose under fasted conditions.
Plasma Cmax and AUC of ertugliflozin increase in a dose-proportional manner following single doses from 0.5 mg to 300 mg and following multiple doses from 1 mg to 100 mg. The absolute oral bioavailability of ertugliflozin following administration of a 15-mg dose is approximately 100%.

Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin C max by 29% and prolongs Tmax by 1 hour but does not alter AUC as compared with the fasted state. The observed effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may be administered with or without food. In Phase 3 clinical trials, ertugliflozin was administered without regard to meals.

Ertugliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters.

Distribution
The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 86 l.
Plasma protein binding of ertugliflozin is 93.6% and is independent of ertugliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The blood-to-plasma concentration ratio of ertugliflozin is 0.66.

Ertugliflozin is not a substrate of organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), or organic anion transporting polypeptides (OATP1B1, OATP1B3) in vitro.

Biotransformation
Metabolism is the primary clearance mechanism for ertugliflozin. The major metabolic pathway for ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to two glucuronides that are pharmacologically inactive at clinically relevant concentrations. CYP-mediated (oxidative) metabolism of ertugliflozin is minimal (12%).

Elimination
The mean systemic plasma clearance following an intravenous 100 µg dose was 11 l/hr. The mean elimination half-life in type 2 diabetic patients with normal renal function was estimated to be 17 hours based on the population pharmacokinetic analysis. Following administration of an oral [14C]-ertugliflozin solution to healthy subjects, approximately 41% and 50% of the drug-related radioactivity was eliminated in faeces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged ertugliflozin in urine and 34% as unchanged ertugliflozin in faeces, which is likely due to biliary excretion of glucuronide metabolites and subsequent hydrolysis to parent.

Special populations

Renal impairment
In a Phase 1 clinical pharmacology study in patients with type 2 diabetes and mild, moderate, or severe renal impairment (as determined by eGFR), following a single-dose administration of 15 mg ertugliflozin, the mean increases in AUC of ertugliflozin were ≤ 1.7-fold, compared to subjects with normal renal function. These increases in ertugliflozin AUC are not considered clinically relevant.
There were no clinically meaningful differences in the ertugliflozin C max values among the different renal function groups. The 24-hour urinary glucose excretion declined with increasing severity of renal impairment (see section 4.4). The plasma protein binding of ertugliflozin was unaffected in patients with renal impairment.


Hepatic impairment
Moderate hepatic impairment (based on the Child-Pugh classification) did not result in an increase in exposure of ertugliflozin. The AUC of ertugliflozin decreased by approximately 13%, and C max decreased by approximately 21% compared to subjects with normal hepatic function. This decrease in ertugliflozin exposure is not considered clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment. The plasma protein binding of ertugliflozin was unaffected in patients with moderate hepatic impairment.

Paediatric population
No studies with ertugliflozin have been performed in paediatric patients.

Effects of age, body weight, gender and race
Based on a population pharmacokinetic analysis, age, body weight, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of ertugliflozin.

Sitagliptin

Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median T max) occurring 1 to 4 hours post-dose. Mean plasma AUC of sitagliptin was 8.52 M•hr and Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87%. Since coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, Steglujan may be administered with or without food.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for C max and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).

Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 l. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79% of sitagliptin is excreted unchanged in the urine.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

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
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 t1/2 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 peptide transporter 1/2 (PEPT1/2) transporters. In vitro, sitagliptin did not inhibit OAT3 (IC 50=160   M) or p-glycoprotein (up to 250 M) 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.

Drug interactions
No drug interactions studies have been performed with Steglujan and other medicinal products; however, such studies have been conducted with the individual active substances.

In vitro assessment of ertugliflozin
In in vitro studies, ertugliflozin and ertugliflozin glucuronides did not inhibit or inactivate CYPs 1A2, 2C9, 2C19, 2C8, 2B6, 2D6, or 3A4, and did not induce CYPs 1A2, 2B6, or 3A4. Ertugliflozin and ertugliflozin glucuronides did not inhibit the activity of UGTs 1A6, 1A9 or 2B7 in vitro. Ertugliflozin was a weak inhibitor of UGTs 1A1 and 1A4 in vitro at higher concentrations that are not clinically relevant. Ertugliflozin glucuronides had no effect on these isoforms. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered drugs eliminated by these enzymes.

Ertugliflozin or ertugliflozin glucuronides do not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 transporters or transporting polypeptides OATP1B1 and OATP1B3 at clinically relevant concentrations in vitro. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are substrates of these transporters.

In vitro assessment of sitagliptin
In vitro data suggest that sitagliptin does not inhibit or induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and OCT. Sitagliptin may be a mild inhibitor of P-gp in vivo.

In vitro transport studies showed that sitagliptin is a substrate for P-gp and OAT3. OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.

Characteristics in patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.

Renal impairment
In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD).

Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased modestly in patients with GFR ≥ 45 to < 90 mL/min. Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is not necessary.

Hepatic impairment
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.


Elderly
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
No studies with sitagliptin have been performed in paediatric patients.

Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These characteristics 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.