Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

14.2 Pharmacodynamics
Empagliflozin
Urinary Glucose Excretion
In patients with type 2 diabetes, 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. 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 recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

Linagliptin
Linagliptin binds to DPP-4 in a reversible manner and increases the concentrations of incretin hormones.
Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion, thus resulting in a better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

Cardiac Electrophysiology
In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg dose.

Pharmacokinetic Properties

14.3 Pharmacokinetics
GLYXAMBI
Administration of the fixed-dose combination with food resulted in no change in overall exposure of empagliflozin or linagliptin; however, the peak exposure was decreased 39% and 32% for empagliflozin and linagliptin, respectively. These changes are not likely to be clinically significant.

Absorption
Empagliflozin
The pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose.
Boehringer Ingeheim Israel                                                                           Page 13 of 27 Glyxambi                                                           Updated Prescribing Information 10 / 5 mg, 25 / 5 mg                                                                     May 2023 Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma AUC and C max were 1870 nmol·h/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4740 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. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.

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.

Linagliptin
The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced C max by 15% and increased AUC by 4%; this effect is not clinically relevant. Linagliptin may be administered with or without food.

Distribution
Empagliflozin
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%.

Linagliptin
The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75% to 89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.

Elimination
Empagliflozin: 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.
Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady- state, which was consistent with empagliflozin half-life.

Linagliptin: Linagliptin has a terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min.

Metabolism
Empagliflozin:
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.



Boehringer Ingeheim Israel                                                                           Page 14 of 27 Glyxambi                                                          Updated Prescribing Information 10 / 5 mg, 25 / 5 mg                                                                    May 2023 Linagliptin:
Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin.

Excretion

Empagliflozin:
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.

Linagliptin
Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing.

Specific Populations
Renal Impairment
GLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and linagliptin after administration of GLYXAMBI in renally impaired patients have not been performed .

Empagliflozin: In patients 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 m 2) renal impairment and patientson 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 subjects 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.

Linagliptin: An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects with normal renal function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with mild renal impairment (CrCl 50 to <80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type 2 diabetes and severe renal impairment (CrCl <30 mL/min), and 11 patients with type 2 diabetes and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.

Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.

In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUCτ,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor.
Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function. Patients with type 2 diabetes and severe renal impairment showed steady-state exposure 
Boehringer Ingeheim Israel                                                                          Page 15 of 27 Glyxambi                                                           Updated Prescribing Information 10 / 5 mg, 25 / 5 mg                                                                     May 2023 approximately 40% higher than that of patients with type 2 diabetes and normal renal function (increase in AUCτ,ss by 42% and Cmax by 35%). For both type 2 diabetes groups, renal excretion was below 7% of the administered dose.

These findings were further supported by the results of population pharmacokinetic analyses.

Hepatic Impairment
GLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and linagliptin after administration of GLYXAMBI in hepatically impaired patients have not been performed.

Empagliflozin: In 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 C max increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.

Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUC τ,ss) of linagliptin was approximately 25% lower and C max,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUC ss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC 0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.

Effects of Age, Body Mass Index, Gender, and Race
Empagliflozin: Based on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have a clinically meaningful effect on pharmacokinetics of empagliflozin [see Use in Specific Populations (11.5)].

Linagliptin: Based on the population PK analysis, age, body mass index (BMI), gender and race do not have a clinically meaningful effect on pharmacokinetics of linagliptin [see Use in Specific Populations (11.5)].

Drug Interactions
Pharmacokinetic drug interaction studies with GLYXAMBI have not been performed; however, such studies have been conducted with the individual components of GLYXAMBI (empagliflozin and linagliptin).

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.


Boehringer Ingeheim Israel                                                                           Page 16 of 27 Glyxambi                                                                       Updated Prescribing Information 10 / 5 mg, 25 / 5 mg                                                                                 May 2023 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 (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.

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%)]


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



Boehringer Ingeheim Israel                                                                                         Page 17 of 27 Glyxambi                                                                        Updated Prescribing Information 10 / 5 mg, 25 / 5 mg                                                                                  May 2023 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 C max Ratios [reference lines indicate 100% (80% - 125%)]


 a empagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, once daily; cempagliflozin, 25 mg, single dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon®; gadministered as ramipril 
Linagliptin
In vitro Assessment of Drug Interactions
Linagliptin is a weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.

Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.

In vivo Assessment of Drug Interactions
Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations [see Drug Interactions (10)]. In vivo studies indicated evidence of a low 
Boehringer Ingeheim Israel                                                                                           Page 18 of 27 Glyxambi                                                                 Updated Prescribing Information 10 / 5 mg, 25 / 5 mg                                                                           May 2023 propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).
Table 4 Effect of Coadministered Drugs on Systemic Exposure of Linagliptin Geometric Mean Ratio
Dosing of Coadministered
Coadministered Drug                                         Dosing of Linagliptina   (ratio with/without coadministered drug) Druga
No effect = 1.0
AUC  d
Cmax
Metformin                   850 mg TID                    10 mg QD                     1.20                       1.03 Glyburide                   1.75 mgc                      5 mg QD                      1.02                       1.01 Pioglitazone                45 mg QD                      10 mg QD                     1.13                       1.07 Ritonavir                   200 mg BID                    5 mgc                        2.01                       2.96 Rifampin  b
600 mg QD                     5 mg QD                      0.60                       0.56 a
Multiple dose (steady-state) unless otherwise noted b
For information regarding clinical recommendations [see Drug Interactions (10)].
c
Single dose d
AUC = AUC(0 to 24 hours) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments 
QD = once daily
BID = twice daily
TID = three times daily

Table 5                     Effect of Linagliptin on Systemic Exposure of Coadministered Drugs 
Geometric Mean Ratio
Dosing of Coadministered
Coadministered Drug                                         Dosing of Linagliptina   (ratio with/without coadministered drug) Druga
No effect = 1.0
AUCc          Cmax
Metformin                   850 mg TID                     10 mg QD                  metformin          1.01             0.89 Glyburide                   1.75 mg   b
5 mg QD                   glyburide          0.86             0.86 pioglitazone       0.94             0.86
Pioglitazone                45 mg QD                       10 mg QD                  metabolite M-III   0.98             0.96 metabolite M-IV    1.04             1.05
Digoxin                     0.25 mg QD                     5 mg QD                   digoxin            1.02             0.94 simvastatin        1.34             1.10
Simvastatin                 40 mg QD                       10 mg QD simvastatin acid   1.33             1.21
R-warfarin         0.99             1.00
S-warfarin         1.03             1.01
Warfarin                    10 mgb                         5 mg QD
INR                0.93d            1.04d
PT                 1.03d            1.15d
Ethinylestradiol and        ethinylestradiol 0.03 mg and                             ethinylestradiol   1.01             1.08 5 mg QD levonorgestrel              levonorgestrel 0.150 mg QD                               levonorgestrel     1.09             1.13 a
Multiple dose (steady-state) unless otherwise noted b
Single dose c
AUC = AUC(INF) for single dose treatments and AUC = AUC(TAU) for multiple-dose treatments d
AUC=AUC(0-168) and Cmax = Emax for pharmacodynamic end points
INR = International Normalized Ratio
PT = Prothrombin Time
QD = once daily
TID = three times daily