Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

14.2 Pharmacodynamics
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
TRAJENTA DUO
Administration of linagliptin 2.5 mg/metformin HCl 1,000 mg fixed-dose combination with food resulted in no change in overall exposure of linagliptin. There was no change in metformin AUC; however, mean peak serum concentration of metformin was decreased by 18% when administered with food. A delayed time-to-peak serum concentrations by 2 hours was observed for metformin under fed conditions. These changes are not likely to be clinically significant.

Absorption
Linagliptin
The absolute bioavailability of linagliptin is approximately 30%. Following oral administration, plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half- life (>100 hours), related to the saturable binding of linagliptin to DPP-4. However, the prolonged elimination does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady state plasma concentrations of linagliptin 5 mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady-state compared with the first dose. Plasma AUC of linagliptin increased in a less than dose- Boehringer Ingelheim Israel                                                                            17 Trajenta duo                                                                     Prescribing Information File coated tablets 2.5mg/500mg, 2.5mg/850mg, 2.5mg/1,000mg                              September 2023 proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes mellitus.

Metformin HCl
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 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.

Distribution
Linagliptin
The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1,110 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.

Metformin HCl
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.

Elimination
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.

Metformin HCl: 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
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.

Metformin HCl: 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.


Boehringer Ingelheim Israel                                                                            18 Trajenta duo                                                                      Prescribing Information File coated tablets 2.5mg/500mg, 2.5mg/850mg, 2.5mg/1,000mg                               September 2023 Excretion
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.

Metformin HCl: 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
Renal Impairment
TRAJENTA DUO: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of TRAJENTA DUO in renally impaired patients have not been performed.

Linagliptin: 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 mellitus and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type 2 diabetes mellitus and normal renal function (increase in AUC by 42% and Cmax by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose.

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

Metformin HCl: 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)].

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

Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUCτ,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss, 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 AUC0-24 and approximately 23% lower Cmax compared with healthy subjects.

Boehringer Ingelheim Israel                                                                             19 Trajenta duo                                                                       Prescribing Information File coated tablets 2.5mg/500mg, 2.5mg/850mg, 2.5mg/1,000mg                                September 2023 Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.

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

Effects of Age, Body Mass Index (BMI), Gender and Race
Linagliptin: Based on the population pharmacokinetic analysis, age, BMI, gender, and race do not have a clinically meaningful effect on pharmacokinetics of linagliptin [see Use in Specific Populations (11.5)].

Metformin HCl: Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender.
Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.


Limited data from controlled pharmacokinetic studies of metformin 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
Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of TRAJENTA DUO in pediatric patients have not yet been performed.

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 Caucasians (n=249), Blacks (n=51), and Hispanics (n=24).

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

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.
Boehringer Ingelheim Israel                                                                              20 Trajenta duo                                                                               Prescribing Information File coated tablets 2.5mg/500mg, 2.5mg/850mg, 2.5mg/1,000mg                                        September 2023 

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 propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp, and organic cationic transporter (OCT).

Table 3 describes the effect of coadministered drugs on systemic exposure of linagliptin.

Table 3 Effect of Coadministered Drugs on Systemic Exposure of Linagliptin 
Geometric Mean Ratio
Dosing of
Coadministered                                        Dosing of             (ratio with/without Coadministered
Drug                                                  Linagliptin*          coadministered drug) Drug*
No effect=1.0
AUC†              Cmax
Metformin                    850 mg TID               10 mg QD              1.20              1.03 Glyburide                    1.75 mg#                 5 mg QD               1.02              1.01 Pioglitazone                 45 mg QD                 10 mg QD              1.13              1.07 Ritonavir                    200 mg BID               5 mg#                 2.01              2.96 Rifampin**                   600 mg QD                5 mg QD               0.60              0.56 *Multiple dose (steady state) unless otherwise noted
**For information regarding clinical recommendations [see Drug Interactions (10)].
#
Single dose
†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 4 describes the effect of linagliptin on systemic exposure of coadministered drugs.

Table 4 Effect of Linagliptin on Systemic Exposure of Coadministered Drugs 
Geometric Mean Ratio
Dosing of
Coadministered                                           Dosing of             (ratio with/without Coadministered
Drug                                                    Linagliptin*          coadministered drug) Drug*
No effect=1.0
AUC†      Cmax
Metformin                850 mg TID                  10 mg QD           metformin        1.01      0.89 #
Glyburide                1.75 mg                     5 mg QD            glyburide           0.86           0.86 pioglitazone metabolite M-       0.94           0.86
Pioglitazone             45 mg QD                    10 mg QD           III                 0.98           0.96 metabolite M-       1.04           1.05
IV

Boehringer Ingelheim Israel                                                                                      21 Trajenta duo                                                                                Prescribing Information File coated tablets 2.5mg/500mg, 2.5mg/850mg, 2.5mg/1,000mg                                         September 2023 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 mg#                      5 mg QD
INR                   0.93**         1.04**
PT                    1.03**         1.15** ethinylestradiol 0.03
Ethinylestradiol mg and                                        ethinylestradiol      1.01           1.08 and                                                  5 mg QD levonorgestrel 0.150                          levonorgestrel        1.09           1.13 levonorgestrel mg QD
* Multiple dose (steady state) unless otherwise noted
#
Single dose
†AUC = AUC(INF) for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments **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

Metformin HCl
Table 5 describes the effect of coadministered drugs on plasma metformin systemic exposure.

Table 5 Effect of Coadministered Drugs on Plasma Metformin Systemic Exposure 
Geometric Mean Ratio
Dosing of
Coadministered                                Dosing of             (ratio with/without Coadministered
Drug                                         Metformin*            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)


Boehringer Ingelheim Israel                                                                                       22 Trajenta duo                                                                     Prescribing Information File coated tablets 2.5mg/500mg, 2.5mg/850mg, 2.5mg/1,000mg                              September 2023 
Table 6 describes the effect of metformin on coadministered drug systemic exposure.

Table 6 Effect of Metformin on Coadministered Drug Systemic Exposure
Dosing of                              Geometric Mean Ratio
Coadministered                                             Dosing of
Coadministered                      (ratio with/without metformin)
Drug                                                      Metformin*
Drug*                                     No effect=1.0
AUC†      Cmax
Glyburide            5 mg                    850 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§         1.02 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