Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, sodium glucose co-transporter 2 (SGLT2) inhibitors, ATC code: A10BK04.

Mechanism of action

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.


Pharmacodynamic effects

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

The efficacy and safety of ertugliflozin have been studied in 7 multi-centre, randomised, double-blind, placebo- or active comparator-controlled, phase 3 clinical studies involving 4,863 patients with type 2 diabetes, including a study of 468 patients with moderate renal impairment. The racial distribution was 76.8% White, 13.3% Asian, 5.0% Black and 4.8% other. Hispanic or Latino patients comprised 24.2% of the population. Patients had an average age of 57.8 years (range 21 years to 87 years), with 25.8% of patients ≥ 65 years of age and 4.5% ≥ 75 years of age.

Ertugliflozin has been studied as monotherapy and in combination with metformin and/or a dipeptidyl peptidase 4 (DPP-4) inhibitor. Ertugliflozin has also been studied in combination with current diabetes treatments, including insulin and a sulphonylurea, in patients with type 2 diabetes with moderate renal impairment.

Monotherapy
A total of 461 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a randomised, double-blind, multi-centre, 26-week, placebo-controlled study to evaluate the efficacy and safety of ertugliflozin monotherapy. These patients, who were not receiving any background anti- hyperglycaemic treatment, were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo administered once daily (see Table 2).

Table 2: Results at week 26 from a placebo-controlled monotherapy study of ertugliflozin* 

Ertugliflozin        Ertugliflozin
Placebo
5 mg                 15 mg
HbA1c (%)                                       N = 156             N = 151             N = 153 Baseline (mean)                                    8.2                 8.4                8.1 Change from baseline (LS mean†)                    -0.8                -1.0               0.2 †          ‡                   ‡
Difference from placebo (LS mean ,         -1.0 (-1.2, -0.8)   -1.2 (-1.4, -0.9) 95% CI)
Patients [N (%)] with HbA1c < 7%               44 (28.2)§          54 (35.8)§           20 (13.1) 
Body weight (kg)                                N = 156             N = 152             N = 153 Baseline (mean)                                    94.0                90.6              94.2 Change from baseline (LS mean†)                    -3.2                -3.6               -1.4 †          ‡                   ‡
Difference from placebo (LS mean ,         -1.8 (-2.6, -0.9)   -2.2 (-3.0, -1.3) 95% CI)
* N includes all randomised, treated patients who had at least one measurement of the outcome variable.
†
Least squares means adjusted for time, prior anti-hyperglycaemic medicinal products, 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).


Ertugliflozin as add-on combination therapy with metformin
A total of 621 patients with type 2 diabetes inadequately controlled on metformin monotherapy (≥ 1,500 mg/day) participated in a randomised, double-blind, multi-centre, 26-week, placebo- controlled study to evaluate the efficacy and safety of ertugliflozin in combination with metformin.
Patients were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo administered once daily in addition to continuation of background metformin therapy (see Table 3).

Table 3: Results at week 26 from a placebo-controlled study for ertugliflozin used in combination with metformin*


Ertugliflozin       Ertugliflozin
Placebo
5 mg                15 mg
HbA1c (%)                                      N = 207              N = 205           N = 209 Baseline (mean)                                   8.1                  8.1              8.2 †
Change from baseline (LS mean )                   -0.7                 -0.9            -0.0 †          ‡                    ‡
Difference from placebo (LS mean ,        -0.7 (-0.9, -0.5)    -0.9 (-1.1, -0.7) 95% CI)
Patients [N (%)] with HbA1c < 7%              73 (35.3)§           82 (40.0)§         33 (15.8) 
Body weight (kg)                               N = 207              N = 205           N = 209 Baseline (mean)                                   84.9                 85.3            84.5 †
Change from baseline (LS mean )                   -3.0                 -2.9            -1.3 Difference from placebo (LS mean†,        -1.7‡ (-2.2, -1.1)   -1.6‡ (-2.2, -1.0) 95% CI)
* N includes all randomised, treated patients who had at least one measurement of the outcome variable.
†
Least squares means adjusted for time, prior anti-hyperglycaemic medicinal products, baseline eGFR, menopausal status randomisation stratum, 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).

Active-controlled study of ertugliflozin versus glimepiride as add-on combination therapy with metformin
A total of 1,326 patients with type 2 diabetes inadequately controlled on metformin monotherapy participated in a randomised, double-blind, multi-centre, 52-week, active comparator-controlled study to evaluate the efficacy and safety of ertugliflozin in combination with metformin. These patients, who were receiving metformin monotherapy (≥ 1,500 mg/day), were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg, or glimepiride administered once daily in addition to continuation of background metformin therapy. Glimepiride was initiated at 1 mg/day and titrated up to a maximum dose of 6 or 8 mg/day (depending on maximum approved dose in each country) or a maximum tolerated dose or down-titrated to avoid or manage hypoglycaemia. The mean daily dose of glimepiride was 3.0 mg (see Table 4).

Table 4: Results at week 52 from an active-controlled study comparing ertugliflozin to 

glimepiride as add-on therapy in patients inadequately controlled on metformin* 

Ertugliflozin       Ertugliflozin
Glimepiride
5 mg                15 mg
HbA1c (%)                                         N = 448             N = 440            N = 437 Baseline (mean)                                      7.8                 7.8               7.8 †
Change from baseline (LS mean )                      -0.6                -0.6             -0.7 †                             ‡
Difference from glimepiride (LS mean ,         0.2 (0.1, 0.3)     0.1 (-0.0, 0.2) 95% CI)
Patients [N (%)] with HbA1c < 7%                 154 (34.4)          167 (38.0)         190 (43.5) 
Body weight (kg)                                  N = 448             N = 440            N = 437 Baseline (mean)                                      87.9                85.6             86.8 †
Change from baseline (LS mean )                      -3.0                -3.4              0.9 †                             §
Difference from glimepiride (LS mean ,       -3.9 (-4.4, -3.4)   -4.3 (-4.8, -3.8) 95% CI)
* N includes all randomised, treated patients who had at least one measurement of the outcome variable.
†
Least squares means adjusted for time, prior anti-hyperglycaemic medicinal products, baseline eGFR and the interaction of time by treatment.
‡
Non-inferiority is declared when the upper bound of the two-sided 95% confidence interval (CI) for the mean difference is less than 0.3%.
§ p< 0.001 compared to glimepiride.

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 5).


Table 5: 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          Ertugliflozin 5 mg            15 mg         100 mg           5 mg +                15 mg + Sitagliptin        Sitagliptin 100 mg
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          -1.0            -1.1           -1.1               -1.5                -1.5 mean†)
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
66 (26.4)       79 (31.9)     81 (32.8)       127 (52.3)§           120 (49.2)§ HbA1c < 7%
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          -2.7            -3.7           -0.7               -2.5                -2.9 mean†)
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 6).


Table 6: Results at week 26 from an add-on study of ertugliflozin in combination with metformin and sitagliptin*

Ertugliflozin        Ertugliflozin       Placebo
5 mg                 15 mg
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%         -0.7 (-0.9, -0.5)    -0.8 (-0.9, -0.6) CI)
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%         -2.0‡ (-2.6, -1.4)   -1.7‡ (-2.3, -1.1) CI)
* N includes all randomised, treated patients who had at least one measurement of the outcome variable.
†
Least squares means adjusted for time, prior anti-hyperglycaemic medicinal products, 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 anti-hyperglycaemic treatment, were randomised to ertugliflozin 5 mg or ertugliflozin 15 mg in combination with sitagliptin (100 mg) or to placebo once daily (see Table 7).


Table 7: Results at Week 26 from a combination therapy study of ertugliflozin and sitagliptin* 
Ertugliflozin       Ertugliflozin       Placebo
5 mg               15 mg
+ Sitagliptin       + 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           -1.2 (-1.5, -0.8)   -1.2 (-1.6, -0.9) and 95% 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 ,         -2.0 (-3.0, -1.0)   -2.1 (-3.1, -1.1) 95% CI)
* 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).

Ertugliflozin as add-on combination therapy with insulin (with or without metformin) In an 18-week randomised, double-blind, multi-centre, placebo-controlled, glycaemic sub-study of VERTIS CV, a total of 1,065 patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease with inadequate glycaemic control (haemoglobin A1c [HbA1c] between 7% and 10.5%) with background therapy of insulin ≥20 units/day (59% patients were also on metformin ≥1,500 mg/day) were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg or placebo once daily (see Table 8).

Table 8: Results at Week 18 from an add-on study of ertugliflozin in combination with insulin (with or without metformin) in patients with type 2 diabetes mellitus* 

Ertugliflozin       Ertugliflozin         Placebo
5 mg                15 mg

HbA1c (%)                                          N = 348             N = 370            N = 347 Baseline (mean)                                        8.4                    8.4          8.4 †
Change from baseline (LS mean )                        -0.8                   -0.8         -0.2 †            ‡                   ‡
Difference from placebo (LS mean , 95%        -0.6 (-0.7, -0.4)   -0.6 (-0.8, -0.5) CI)
Patients [N (%)] with HbA1c <7%                   72 (20.7) §        78 (21.1) §         37 (10.7) Body weight (kg)                                   N = 348             N = 370            N = 347 Baseline (mean)                                       93.8                    92.1         93.3 †
Change from baseline (LS mean )                        -1.9                   -2.1         -0.2 †            ‡                   ‡
Difference from placebo (LS mean , 95%        -1.6 (-2.1, -1.1)   -1.9 (-2.4, -1.4) CI)
* N includes all randomised, treated patients who had at least one measurement of the outcome variable.
†
Least squares means adjusted for time, insulin stratum, 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).

Ertugliflozin as add-on combination therapy with metformin and sulphonylurea In an 18-week randomised, double-blind, multi-centre, placebo-controlled, glycaemic sub-study of VERTIS CV, a total of 330 patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease with inadequate glycaemic control (HbA1c between 7% and 10.5%) with background therapy of metformin ≥1,500 mg/day and a sulphonylurea were randomised to ertugliflozin 5 mg, ertugliflozin 15 mg or placebo once daily (see Table 9).

Table 9: Results at Week 18 from an add-on study of ertugliflozin in combination with metformin and a sulphonylurea in patients with type 2 diabetes mellitus* 

Ertugliflozin        Ertugliflozin         Placebo
5 mg                 15 mg

HbA1c (%)                                            N = 100              N = 113            N = 117 Baseline (mean)                                      8.4                  8.3              8.3 †
Change from baseline (LS mean )                      -0.9                 -1.0             -0.2 Difference from placebo (LS mean†, 95%       -0.7‡ (-0.9, -0.4)   -0.8‡ (-1.0, -0.5) CI)
§                    §
Patients [N (%)] with HbA1c <7%                     37 (37.0)            37 (32.7)          15 (12.8) Body weight (kg)                                     N = 100              N = 113            N = 117 Baseline (mean)                                      92.1                 92.9             90.5 †
Change from baseline (LS mean )                      -2.0                 -2.4             -0.5 †            ‡                    ‡
Difference from placebo (LS mean , 95%       -1.6 (-2.3, -0.8)    -1.9 (-2.6, -1.2) 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 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).

Moderate renal impairment
The efficacy of ertugliflozin was also assessed separately in a dedicated study of diabetic patients with moderate renal impairment (468 patients with eGFR ≥ 30 to < 60 mL/min/1.73 m2).

The least square (LS) mean (95% CI) changes from baseline in HbA1c were -0.26 (-0.42, -0.11), -0.29 (-0.44, -0.14), and -0.41 (-0.56, -0.27) in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively. The HbA1c reductions in the ertugliflozin arms were not significantly different from placebo. The pre-specified analysis of glycaemic efficacy was confounded by use of prohibited concomitant anti-hyperglycaemic medicinal products. In a subsequent analysis excluding those subjects who used the prohibited medicinal products, ertugliflozin 5 mg and 15 mg were associated with placebo-corrected reductions in HbA1c of -0.14 (-0.36, 0.08) and -0.33 (-0.55, -0.11).

Fasting plasma glucose
In three placebo-controlled studies, ertugliflozin resulted in statistically significant reductions in fasting plasma glucose (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 ≥ 8%
In the monotherapy study conducted on a background of diet and exercise in patients with baseline HbA1c from 7-10.5%, the subgroup of patients in the study with a baseline HbA1c ≥ 8% had placebo-corrected reductions in HbA1c of 1.11% and 1.52% with ertugliflozin 5 or 15 mg, respectively.

In the study of ertugliflozin added-on to metformin in patients with baseline HbA1c from 7-10.5%, the placebo-corrected reductions in HbA1c for the subgroup of patients in the study with baseline HbA1c ≥ 9% were 1.31% and 1.43% with ertugliflozin 5 and 15 mg, respectively.

In the study of patients inadequately controlled on metformin with baseline HbA1c from 7.5-11%, 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% compared to 2.10%, 1.30%, and 1.82% for ertugliflozin 5 mg, ertugliflozin 15 mg and sitagliptin alone, respectively.

Post-prandial glucose
In the monotherapy study, 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.

Blood pressure
In three 26-week, placebo-controlled studies, ertugliflozin reduced systolic blood pressure (SBP). For ertugliflozin 5 mg and 15 mg, the statistically significant placebo-corrected reductions in SBP ranged from 2.9 mmHg to 3.7 mmHg and 1.7 mmHg to 4.5 mmHg, respectively.


In a 52-week, active-controlled study versus glimepiride, reductions from baseline in SBP were 2.2 mmHg and 3.8 mmHg for ertugliflozin 5 mg and 15 mg respectively, while subjects treated with glimepiride had an increase in SBP from baseline of 1.0 mmHg.

Subgroup analysis
In patients with type 2 diabetes treated with ertugliflozin, clinically meaningful reductions in HbA1c were observed in subgroups defined by age, sex, race, ethnicity, geographic region, baseline body mass index (BMI), baseline HbA1c, and duration of type 2 diabetes mellitus.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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 time to maximum plasma concentration [Tmax]) of ertugliflozin occur at 1 hour post-dose under fasted conditions. Plasma C max 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.

Drug interactions

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 medicinal products 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 medicinal products that are substrates of these transporters.