Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
General
In patients with type 2 diabetes mellitus, 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.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.
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 how these findings relate to changes in glycemic control in patients with type 2 diabetes mellitus.
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 was observed at 3 hours postdose and 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 mellitus 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
The pharmacokinetics of sitagliptin have been extensively characterized in healthy subjects and patients with type 2 diabetes mellitus. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 μM•hr, Cmax was 950 nM, and apparent terminal half- life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased in a dose-proportional manner and increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes mellitus.
Absorption
After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. The absolute bioavailability of sitagliptin is approximately 87%.
Effect of Food
Coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin.
Distribution
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%).
Elimination
Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination. 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.
Metabolism
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.
Excretion
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.
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 (P-gp), which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a P-gp inhibitor, did not reduce the renal clearance of sitagliptin.
Specific Populations
Patients with Renal Impairment
An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment with eGFR of 30 to less than 45 mL/min/1.73 m², 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.
Patients with Hepatic Impairment
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).
Effects of Age, Body Mass Index (BMI), Gender, and Race
Based on a population pharmacokinetic analysis or a composite analysis of available pharmacokinetic data, BMI, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of 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.
Drug Interaction Studies
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-gp substrate, but does not inhibit P-gp 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
Effects of Sitagliptin on Other Drugs
In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, digoxin, warfarin, or an oral contraceptive (ethinyl estradiol and norethindrone) (Table 4), providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, and organic cationic transporter (OCT).
Table 4:
Effect of Sitagliptin on Systemic Exposure of Coadministered Drugs
Coadministered           Dose of              Dose of                  Geometric Mean Ratio Drug                  Coadministered        Sitagliptin*           (ratio with/without sitagliptin) Drug*                                            No Effect = 1.00
AUC†          Cmax
Digoxin                0.25 mg‡ once       100 mg‡ once       Digoxin             1.11§        1.18 daily for 10 days   daily for 10 days
Glyburide                 1.25 mg          200 mg‡ once       Glyburide           1.09         1.01 daily for 6 days
Simvastatin                20 mg           200 mg‡ once       Simvastatin         0.85¶        0.80 daily for 5 days    Simvastatin         1.12¶        1.06
Acid
Rosiglitazone               4 mg           200 mg‡ once       Rosiglitazone       0.98         0.99 daily for 5 days
Warfarin              30 mg single dose    200 mg‡ once       S(-) Warfarin       0.95         0.89 on day 5       daily for 11 days   R(+) Warfarin       0.99         0.89 Ethinyl estradiol    21 days once daily    200 mg‡ once       Ethinyl             0.99         0.97 and norethindrone      of 35 µg ethinyl   daily for 21 days   estradiol estradiol with                        Norethindrone       1.03         0.98 norethindrone 0.5
mg x 7 days, 0.75
mg x 7 days, 1.0
mg x 7 days
Metformin HCl          1000 mg‡ twice       50 mg‡ twice      Metformin           1.02#        0.97 daily for 14 days   daily 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.

Effects of Other Drugs on Sitagliptin
Clinical data described below suggest that sitagliptin is not susceptible to clinically meaningful interactions by coadministered medications (Table 5).
Table 5:
Effect of Coadministered Drugs on Systemic Exposure of Sitagliptin
Coadministered           Dose of               Dose of                  Geometric Mean Ratio Drug                  Coadministered         Sitagliptin*        (ratio with/without coadministered Drug*                                                 drug)
No Effect = 1.00
AUC†         Cmax
Cyclosporine         600 mg once daily 100 mg once daily Sitagliptin           1.29          1.68 Metformin HCl         1000 mg‡ twice       50 mg‡ twice daily Sitagliptin      1.02§         1.05 daily 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.
§
AUC0-12hr.