Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

14.2 Pharmacodynamics
Urinary Glucose Excretion
In patients with type 2 diabetes mellitus,, urinary glucose excretion increased immediately following a dose of empagliflozin and was maintained at the end of a 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily [see Clinical Studies (16)]. Data from single oral doses of empagliflozin in healthy subjects indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg and 25 mg doses.

Urinary Volume
In a 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of empagliflozin 25 mg once daily treatment.
Cardiac Electrophysiology
In a randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered a single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

Pharmacokinetic Properties

14.3 Pharmacokinetics
The pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes mellitus and no clinically relevant differences were noted between the two populations. The steady-state mean plasma AUC and Cmax were 1,870 nmol·h/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4,740 nmol·h/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. Empagliflozin does not appear to have time-dependent pharmacokinetic characteristics. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state.



Boehringer Ingelheim Israel                                                            Page 14 of 44 Jardiance                                                          Updated Prescribing Information 10 mg, 25 mg                                                                              Feb 2024 Absorption
After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post- dose.
Administration of 25 mg empagliflozin after intake of a high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and C max decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.
Distribution
The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.
Elimination
The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis.
Metabolism
No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho- glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.
Excretion
Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.
Specific Populations
Pediatric Patients
The pharmacokinetics and pharmacodynamics of empagliflozin were investigated in pediatric patients aged 10 to 17 years with type 2 diabetes mellitus. Oral administration of empagliflozin at 10 mg resulted in exposure within the range observed in adult patients.
Effects of Age, Body Mass Index, Gender, and Race
Age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have a clinically meaningful effect on pharmacokinetics of empagliflozin.
Patients with Hepatic Impairment
In adult patients with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.
Patients with Renal Impairment
In adult patients with type 2 diabetes mellitus with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and patients on dialysis due to kidney failure, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal 
Boehringer Ingelheim Israel                                                           Page 15 of 44 Jardiance                                                            Updated Prescribing Information 10 mg, 25 mg                                                                                Feb 2024 function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and patients on dialysis due to kidney failure compared to subjects with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in patients with mild and severe renal impairment as compared to patients with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with a decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.
Drug Interactions Studies
In vitro Assessment of Drug Interactions
Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho- glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated.
Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2.
Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters.
In vivo Assessment of Drug Interactions
Empagliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes mellitus (see Figure 1). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in a 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion. The relevance of this observation to patients with renal impairment is unknown.



Boehringer Ingelheim Israel                                                             Page 16 of 44 Jardiance                                                                               Updated Prescribing Information 10 mg, 25 mg                                                                                                   Feb 2024 Figure 1          Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and C max Ratios [reference lines indicate 100% (80% - 125%)]
Geometric mean ratio (90% confidence interval)


Antidiabetic drugs        Metformin, 1000 mg, twice dailya         AUC Cmax

Glimepiride, 1 mg, single dosea          AUC
Cmax

Pioglitazone, 45 mg, once dailya         AUC
Cmax
Sitagliptin, 100 mg, once dailya         AUC
Cmax

Linagliptin, 5 mg, once dailya           AUC
Cmax

Others                    Simvastatin, 40 mg, single doseb         AUC Cmax

Warfarin, 25 mg, single dosec            AUC
Cmax

Verapamil, 120 mg, single doseb          AUC
Cmax
Ramipril, 5 mg, once dailyc              AUC
Cmax

Gemfibrozil, 600 mg, twice dailyb        AUC
Cmax

Hydrochlorothiazide, 25mg, once dailyc   AUC
Cmax

Torasemide, 5 mg, once dailyc            AUC
Cmax

Rifampicin, 600 mg, single dosed         AUC
Cmax

Probenecid, 500 mg, twice dailyd         AUC
Cmax


50       75      100      125      150      175          200
Change relative to empagliflozin alone


 a empagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; d empagliflozin, 10 mg, single dose
Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (see Figure 2).



Boehringer Ingelheim Israel                                                                                   Page 17 of 44 Jardiance                                                                                  Updated Prescribing Information 10 mg, 25 mg                                                                                                      Feb 2024 Figure 2             Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% - 125%)]
Geometric mean ratio (90% confidence interval)


Antidiabetic drugs       Metformin, 1000 mg, twice dailya          AUC Cmax

Glimepiride, 1 mg, single dosea            AUC
Cmax

Pioglitazone, 45 mg, once dailyb           AUC
Cmax
Sitagliptin, 100 mg, once dailya           AUC
Cmax

Linagliptin, 5 mg, once dailya            AUC
Cmax

Oral contraceptives      Ethinylestradiol, 30 mcg, once dailyb,f   AUC Cmax

Levonorgestrel, 150 mcg, once dailyb,f    AUC
Cmax

Others                   Simvastatin, 40 mg, single dosec          AUC Cmax

Simvastatin acidd                         AUC
Cmax

R-Warfarin, 25 mg, single doseb,e         AUC
Cmax b,e
S-Warfarin, 25 mg, single dose             AUC
Cmax
Ramipril, 5 mg, once dailyb               AUC
Cmax

Ramiprilatg                               AUC
Cmax

Digoxin, 0.5 mg, single doseb             AUC
Cmax
Hydrochlorothiazide, 25 mg, once dailyb   AUC
Cmax

Torasemide, 5 mg, once dailyb              AUC
Cmax


50           75            100          125               150

 a empagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, once daily; cempagliflozin, 25 mg, single dose; d administered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon®; g administered as ramipril