Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Sitagliptin
General
In patients with type 2 diabetes, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
Sitagliptin and Metformin hydrochloride Coadministration
In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents.
Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.
Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear what these findings mean for changes in glycemic control in patients with type 2 diabetes.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.
Cardiac Electrophysiology
In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800-mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hours postdose was 8.0 msec. This increase is not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose.
In patients with type 2 diabetes administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

Pharmacokinetic Properties

12.3 Pharmacokinetics
JANUET
The results of a bioequivalence study in healthy subjects demonstrated that the JANUET (sitagliptin and metformin HCl) 50 mg/500 mg and 50 mg/1000 mg combination tablets are bioequivalent to coadministration of corresponding doses of sitagliptin (JANUVIA®) and metformin hydrochloride as individual tablets.
Absorption
Sitagliptin
The absolute bioavailability of sitagliptin is approximately 87%. Coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin.
Metformin hydrochloride
The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1500 mg, and 850 mg to 2550 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 mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (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
Sitagliptin
The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Metformin hydrochloride
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism
Sitagliptin
Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Metformin hydrochloride
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.
Excretion
Sitagliptin
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
Metformin hydrochloride
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with 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.
Specific Populations
Renal Impairment
JANUET
JANUET should not be used in patients with renal impairment [see Contraindications (4); Warnings and Precautions (5.4)].
Sitagliptin
An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment, and an approximately 4-fold increase was observed in patients with severe renal impairment including patients with ESRD on hemodialysis, as compared to normal healthy control subjects.
Metformin hydrochloride
In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Hepatic Impairment
Sitagliptin
In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100-mg dose of sitagliptin. These differences are not considered to be clinically meaningful.
There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9).
Metformin hydrochloride
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Gender
Sitagliptin
Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Metformin hydrochloride
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Geriatric
Sitagliptin
When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis.
Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Metformin hydrochloride
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 to 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.
As is true for all patients, JANUET treatment should not be initiated in geriatric patients unless measurement of creatinine clearance demonstrates that renal function is normal [see Warnings and Precautions (5.1, 5.4)].
Pediatric
No studies with JANUET have been performed in pediatric patients.
Race
Sitagliptin
Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.
Metformin hydrochloride
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).
Body Mass Index (BMI)
Sitagliptin
Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Drug Interactions
Sitagliptin and Metformin hydrochloride
Coadministration of multiple doses of sitagliptin (50 mg) and metformin (1000 mg) given twice daily did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes.
Pharmacokinetic drug interaction studies with JANUET have not been performed; however, such studies have been conducted with the individual components of JANUET (sitagliptin and metformin hydrochloride).
Sitagliptin
In Vitro Assessment of Drug Interactions
Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.
In Vivo Assessment of Drug Interactions

Table 4: Effect of Sitagliptin on Systemic Exposure of Coadministered Drugs 
Coadministered Drug            Dose of                 Dose of                         Geometric Mean Ratio Coadministered            Sitagliptin*                 (ratio with/without sitagliptin) Drug*                                                      No Effect = 1.00 †
AUC              Cmax

No dosing adjustments required for the following:
‡                    ‡                                               § Digoxin                    0.25 mg once daily     100 mg once daily      Digoxin                   1.11            1.18 for 10 days           for 10 days
‡
Glyburide                         1.25 mg         200 mg once daily      Glyburide                 1.09            1.01 for 6 days
‡                                               ¶
Simvastatin                        20 mg          200 mg once daily      Simvastatin               0.85            0.80 ¶ for 5 days        Simvastatin Acid          1.12            1.06
‡
Rosiglitazone                       4 mg          200 mg once daily      Rosiglitazone             0.98            0.99 for 5 days
‡
Warfarin                  30 mg single dose on    200 mg once daily      S(-) Warfarin             0.95            0.89 day 5              for 11 days        R(+) Warfarin             0.99            0.89 ‡
Ethinyl estradiol and     21 days once daily of   200 mg once daily      Ethinyl estradiol         0.99            0.97 norethindrone                  35 µg ethinyl          for 21 days        Norethindrone             1.03            0.98 estradiol with norethindrone 0.5 mg x 7 days, 0.75 mg x 7 days, 1.0 mg x 7 days
‡                   ‡                                                # Metformin                 1000 mg twice daily      50 mg twice daily     Metformin                 1.02            0.97 for 14 days            for 7 days
*    All doses administered as single dose unless otherwise specified.
†
AUC is reported as AUC0-∞ unless otherwise specified.
‡
Multiple dose.
§
AUC0-24hr.
¶
AUC0-last.
#
AUC0-12hr.
Table 5: Effect of Coadministered Drugs on Systemic Exposure of Sitagliptin 
Coadministered               Dose of            Dose of Sitagliptin*                Geometric Mean Ratio Drug                      Coadministered                                  (ratio with/without coadministered drug) Drug*                                                    No Effect = 1.00 †
AUC            Cmax

No dosing adjustments required for the following:
Cyclosporine             600 mg once daily       100 mg once daily      Sitagliptin         1.29             1.68 ‡                    ‡                                          § Metformin              1000 mg twice daily      50 mg twice daily for   Sitagliptin         1.02             1.05 for 14 days                 7 days
* All doses administered as single dose unless otherwise specified.
†
AUC is reported as AUC0-∞ unless otherwise specified.
‡
Multiple dose.
§
AUC0-12hr.

Table 6: Effect of Metformin on Systemic Exposure of Coadministered Drugs 
Coadministered Drug           Dose of            Dose of Metformin*                   Geometric Mean Ratio Coadministered                                        (ratio with/without metformin) Drug*                                                     No Effect = 1.00 †
AUC            Cmax

No dosing adjustments required for the following:
‡
Cimetidine                        400 mg                   850 mg    Cimetidine               0.95           1.01 ¶                                 §              §
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 * All doses administered as single dose unless otherwise specified.
†
AUC is reported as AUC0-∞ unless otherwise specified.
‡
AUC0-24hr.
§
Ratio of arithmetic means, p value of difference <0.05.
¶
GLUMETZA (metformin hydrochloride extended-release tablets) 500 mg.
#
Ratio of arithmetic means.


Table 7: Effect of Coadministered Drugs on Systemic Exposure of Metformin 
Coadministered               Dose of              Dose of                         Geometric Mean Ratio Drug                      Coadministered         Metformin*             (ratio with/without coadministered drug) Drug*                                                  No Effect = 1.00 †
AUC          Cmax

No dosing adjustments required for the following:
‡               ‡                     §              §
Glyburide                      5 mg                500 mg       Metformin                  0.98           0.99 §              §
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: use with caution. [See Warnings and Precautions (5.10) and Drug Interactions (7.2).]
Cimetidine                     400 mg               850 mg         Metformin                   1.40   1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis: use with caution. [See Warnings and Precautions (5.1) and Drug Interactions (7.1).]
¶                   ¶                                         ¶
Topiramate                     100 mg              500 mg          Metformin                   1.25   1.17 * All doses administered as single dose unless otherwise specified.
†
AUC is reported as AUC0-∞ unless otherwise specified.
‡
GLUMETZA (metformin hydrochloride extended-release tablets) 500 mg.
§
Ratio of arithmetic means.
¶
Steady state 100 mg Topiramate every 12 hr + metformin 500 mg every 12 hr AUC = AUC0-12hr.