Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

15.2 Pharmacodynamics
Empagliflozin
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 (17)]. 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

15.3 Pharmacokinetics
JARDIANCE DUO
Administration of 12.5 mg empagliflozin/1,000 mg metformin HCl under fed conditions resulted in a 9% decrease in AUC and a 28% decrease in Cmax for empagliflozin, when compared to fasted conditions. For metformin, AUC decreased by 12% and Cmax decreased by 26% compared to fasting conditions. The observed effect of food on empagliflozin and metformin is not considered to be clinically relevant.

Empagliflozin
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 Jardiance Duo                                                                      Updated prescribing information 5mg/850mg, 5mg/1000mg, 12.5mg/850mg, 12.5mg/1000mg                                                       May 2024 pharmacokinetic characteristics. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state.

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 Cmax 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.

Metformin
Absorption
The absolute bioavailability of a metformin HCl 500-mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin HCl tablets 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.

Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower Cmax, a 25% lower AUC, and a 35 minute prolongation of time to peak plasma concentration
(Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution
The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin HCl tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins.
Metformin partitions into erythrocytes, most likely as a function of time.


Jardiance Duo                                                                       Updated prescribing information 5mg/850mg, 5mg/1000mg, 12.5mg/850mg, 12.5mg/1000mg                                                        May 2024 Elimination
Metformin has a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Metabolism Intravenous single-dose studies in normal subjects demonstrate that metformin does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Excretion Following oral administration, approximately 90% of the absorbed drug is excreted via the renal route within the first 24 hours. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination.

Specific Populations
Geriatric Patients
JARDIANCE DUO: Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of JARDIANCE DUO in geriatric patients have not been performed [see Warnings and Precautions (8.2) and Use in Specific Populations (11.5)].

Empagliflozin: Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on a population pharmacokinetic analysis [see Use in Specific Populations (11.5)].

Metformin HCl: Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

Pediatric Patients
Studies characterizing the pharmacokinetics of empagliflozin or metformin after administration of JARDIANCE DUO in pediatric patients have not been performed.

Effects of Age, Body Mass Index, Gender, and Race
Empagliflozin: Age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have a clinically meaningful effect on pharmacokinetics of empagliflozin.

Metformin HCl: No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin HCl in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Blacks or African Americans (n=51), and Hispanics or latinos (n=24).

Patients with Renal Impairment
JARDIANCE DUO: Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of JARDIANCE DUO in renally impaired patients have not been performed.
Empagliflozin: 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 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 Jardiance Duo                                                                      Updated prescribing information 5mg/850mg, 5mg/1000mg, 12.5mg/850mg, 12.5mg/1000mg                                                       May 2024 exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.

Metformin: In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (7) and Warnings and Precautions (8.1)].

Patients with Hepatic Impairment
JARDIANCE DUO: Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of JARDIANCE DUO in hepatically impaired patients have not been performed [see Warnings and Precautions (8.1)].

Empagliflozin: 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.

Metformin HCl: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

Drug Interaction Studies
Pharmacokinetic drug interaction studies with JARDIANCE DUO have not been performed; however, such studies have been conducted with the individual components empagliflozin and metformin HCl.

Empagliflozin
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 HCl, 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.

Jardiance Duo                                                                     Updated prescribing information 5mg/850mg, 5mg/1000mg, 12.5mg/850mg, 12.5mg/1000mg                                                      May 2024 Figure 1          Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% - 125%)]


 a empagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; d empagliflozin, 10 mg, single dose



Jardiance Duo                                                                     Updated prescribing information 5mg/850mg, 5mg/1000mg, 12.5mg/850mg, 12.5mg/1000mg                                                      May 2024 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).

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%)]


 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



Jardiance Duo                                                                Updated prescribing information 5mg/850mg, 5mg/1000mg, 12.5mg/850mg, 12.5mg/1000mg                                                 May 2024 Metformin HCl

Table 5         Effect of Coadministered Drug on Plasma Metformin Systemic Exposure 
Geometric Mean Ratio
Dose of
Coadministered                               Dose of Metformin         (ratio with/without Coadministered
Drug                                            HCl*              coadministered drug) Drug*
No effect=1.0
AUC†        Cmax

Glyburide             5 mg                    850 mg              metformin       0.91‡      0.93‡ Furosemide            40 mg                   850 mg              metformin       1.09‡      1.22‡ Nifedipine            10 mg                   850 mg              metformin       1.16       1.21 Propranolol           40 mg                   850 mg              metformin       0.90       0.94 Ibuprofen             400 mg                  850 mg              metformin       1.05‡      1.07‡ Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [see Drug Interactions (10)].
Cimetidine            400 mg                  850 mg              metformin       1.40       1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see Drug Interactions (10)].
Topiramate**          100 mg                  500 mg              metformin       1.25       1.17 * All metformin and coadministered drugs were given as single doses
† AUC = AUC(INF)
‡ Ratio of arithmetic means
**At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC(0-12 hours)



Jardiance Duo                                                                    Updated prescribing information 5mg/850mg, 5mg/1000mg, 12.5mg/850mg, 12.5mg/1000mg                                                     May 2024 Table 6       Effect of Metformin on Coadministered Drug Systemic Exposure 
Dose of                                          Geometric Mean Ratio Coadministered                                 Dose of Metformin
Coadministered                                  (ratio with/without metformin) Drug                                             HCl*
Drug*                                                No effect=1.0
AUC†       Cmax

Glyburide            5 mg                      500 mg§               glyburide        0.78‡          0.63‡ Furosemide           40 mg                     850 mg                furosemide       0.87‡          0.69‡ Nifedipine           10 mg                     850 mg                nifedipine       1.10§          1.08 Propranolol          40 mg                     850 mg                propranolol      1.01§          0.94 Ibuprofen            400 mg                    850 mg                ibuprofen        0.97¶          1.01¶ Cimetidine           400 mg                    850 mg                cimetidine       0.95§          1.01 * All metformin and coadministered drugs were given as single doses
† AUC = AUC(INF) unless otherwise noted
‡ Ratio of arithmetic means, p-value of difference <0.05
§ AUC(0-24 hours) reported
¶ Ratio of arithmetic means