Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

11.2 Pharmacodynamics

General
Dapagliflozin
Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions (6.1)]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose.
Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot)



Cardiac Electrophysiology
Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15-times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50-times the recommended maximum dose) of dapagliflozin in healthy subjects.

Pharmacokinetic Properties

11.3 Pharmacokinetics
XIGDUO XR

The administration of XIGDUO XR in healthy subjects after a standard meal compared to the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin extended-release. Compared to the fasted state, the standard meal resulted in 35% reduction and a delay of 1 to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is not considered to be clinically meaningful.
Food has no relevant effect on the pharmacokinetics of metformin when administered as XIGDUO XR combination tablets.
Absorption

Dapagliflozin

Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within 2 hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is
78%. Administration of dapagliflozin with a high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.
Metformin hydrochloride

Following a single oral dose of metformin extended-release, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. The extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food. There was no effect of food on Cmax and Tmax of metformin.

Distribution

Dapagliflozin
Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.
Metformin hydrochloride

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 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.

Metabolism
Dapagliflozin

The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3- O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.
Metformin hydrochloride

Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Metabolism studies with extended-release metformin tablets have not been conducted.
Elimination
Dapagliflozin

Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg.
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
Dapagliflozin
At steady-state (20 mg once daily dapagliflozin for 7 days), patients with type 2 diabetes mellitus with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 100%, and 200% higher, respectively, as compared to patients with type 2 diabetes with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.4), Warnings and Precautions (5.3), and Use in Specific Populations (8.6) and Clinical studies (14)].
Metformin hydrochloride

In patients with decreased renal function the plasma and blood half-life of metformin is prolonged, and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1)].

Hepatic Impairment
Dapagliflozin

In patients with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls.
Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see Warnings and Precautions (5.1)].
Geriatric
Dapagliflozin

Based on a population pharmacokinetic analysis, age does not have a clinically meaningful effect on systemic exposures of dapagliflozin.
Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggests 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.
Pediatric
Pharmacokinetics of XIGDUO XR in the pediatric population has not been studied.

Gender
Dapagliflozin

Based on a population pharmacokinetic analysis, gender does not have a clinically meaningful effect on systemic exposures of dapagliflozin.
Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Race
Dapagliflozin

Based on a population pharmacokinetic analysis, race (White, Black, or Asian) does not have a clinically meaningful effect on systemic exposures of dapagliflozin.
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 mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).

Body Weight
Dapagliflozin

Based on a population pharmacokinetic analysis, body weight does not have a clinically meaningful effect on systemic exposures of dapagliflozin.
Drug Interactions
Specific pharmacokinetic drug interaction studies with XIGDUO XR have not been performed, although such studies have been conducted with the individual dapagliflozin and metformin components.

In Vitro Assessment of Drug Interactions
Dapagliflozin

In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P- gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter.
Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.

Effects of Other Drugs on Metformin
Table 7 shows the effect of other coadministered drugs on metformin.

Table 7: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug (Dose Regimen)1                                  Metformin                      Metformin (Dose                 Change2 in          Change2
Regimen)1                 AUC3              in Cmax
No dosing adjustments required for the following:
Glyburide (5 mg)                                                       850 mg                        4                   4 ↓9%               ↓7%
Furosemide (40 mg)                                                     850 mg                          4                 4 ↑15%              ↑22%
Nifedipine (10 mg)                                                     850 mg                    ↑9%              ↑20% Propranolol (40 mg)                                                    850 mg                   ↓10%               ↓6% Ibuprofen (400 mg)                                                     850 mg                        4                   4 ↑5%            ↑7%
Drugs eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7.)].
Cimetidine (400 mg)                                                    850 mg                   ↑40%              ↑60% 1.   All metformin and co-administered drugs were given as single doses.
2.   Percent change (with/without co-administered drug and no change = 0%); ↑ and ↓ indicate the exposure increase and decrease, respectively.
3.   AUC = AUC(INF).
4.   Ratio of arithmetic means.
Effects of Metformin on Other Drugs
Table 8 shows the effect of metformin on other co-administered drugs.

Table 8: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug (Dose Regimen)1                                    Metformin              Coadministered Drug (Dose              Change2 in        Change2 in
Regimen)1              AUC3              Cmax
No dosing adjustments required for the following:

Glyburide (5 mg)                                                         850 mg                       4                 4 ↓22%              ↓37%
Furosemide (40 mg)                                                       850 mg                       4                 4 ↓12%              ↓31%
Nifedipine (10 mg)                                                       850 mg                       5           ↑8% ↑10%
Propranolol (40 mg)                                                      850 mg                      5            ↑2% ↑1%
Ibuprofen (400 mg)                                                       850 mg                      6                  6 ↓3%              ↑1%
Cimetidine (400 mg)                                                      850 mg                      5 ↓5%               ↑1%
1.
All metformin and coadministered drugs were given as single doses.
2.   Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure increase and decrease, respectively.
3.   AUC = AUC(INF) unless otherwise noted.
4.   Ratio of arithmetic means, p-value of difference <0.05.
5.   AUC(0-24 hr) reported.
6.   Ratio of arithmetic means.

Effects of Other Drugs on Dapagliflozin
Table 9 shows the effect of coadministered drugs on dapagliflozin. No dose adjustments are recommended for dapagliflozin.


Table 9: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure Coadministered Drug (Dose Regimen)1                                   Dapagliflozin                Dapagliflozin (Dose
Change2 in         Change2 in
Regimen)1
AUC3               Cmax
No dosing adjustments required for the following:

Oral Antidiabetic Agents

Metformin (1000 mg)                                                      20 mg                 ↓1%               ↓7% Pioglitazone (45 mg)                                                     50 mg                 0%                ↑9% Sitagliptin (100 mg)                                                     20 mg                 ↑8%               ↓4% Glimepiride (4 mg)                                                       20 mg                 ↓1%               ↑1% Voglibose (0.2 mg three times daily)                                     10 mg                 ↑1%               ↑4% Other Medications

Hydrochlorothiazide (25 mg)                                              50 mg                 ↑7%               ↓1% Bumetanide (1 mg)                                                     10 mg once              ↑5%               ↑8% daily for 7 days
Valsartan (320 mg)                                                       20 mg                ↑2%              ↓12% Simvastatin (40 mg)                                                      20 mg                ↓1%               ↓2% Anti-infective Agent

Rifampin (600 mg once daily for 6 days)                                  10 mg               ↓22%               ↓7% 
Nonsteroidal Anti-inflammatory Agent

Mefenamic Acid (loading dose of                                          10 mg               ↑51%              ↑13% 500 mg followed by 14 doses of
250 mg every 6 hours)
1.   Single dose unless otherwise noted.
2.   Percent change (with/without co-administered drug and no change = 0%); ↑ and ↓ indicate the exposure increase and decrease, respectively.
3.   AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.

Effects of Dapagliflozin on Other Drugs
Table 10 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.


Table 10: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs Coadministered Drug (Dose Regimen)1                                     Dapagliflozin            Co-administered Drug (Dose
Regimen)1           Change2 in          Change2 in
AUC3                  Cmax
No dosing adjustments required for the following:

Oral Antidiabetic Agents

Metformin (1000 mg)                                                   20 mg                 0%                ↓5% 
Pioglitazone (45 mg)                                                  50 mg                 0%                ↓7% 
Sitagliptin (100 mg)                                                  20 mg                 ↑1%              ↓11% 
Glimepiride (4 mg)                                                    20 mg                ↑13%               ↑4% 
Other Medications

Hydrochlorothiazide (25 mg)                                           50 mg                 ↓1%               ↓5% 
Bumetanide (1 mg)                                                10 mg once daily          ↑13%              ↑13% for 7 days
Valsartan (320 mg)                                                    20 mg                 ↑5%               ↓6% 
Simvastatin (40 mg)                                                   20 mg                ↑19%               ↓6% Digoxin (0.25 mg)                                                  20 mg loading              0%               ↓1% dose then 10 mg once daily for 7 days
Warfarin (25 mg)                                                   20 mg loading S-warfarin                                                     dose then 10 mg ↑3%               ↑7%
R-warfarin                                                     once daily for 7 days                 ↑6%               ↑8%
1.   Single dose unless otherwise noted.
2.   Percent change (with/without co-administered drug and no change = 0%); ↑ and ↓ indicate the exposure increase and decrease,
respectively.
3.   AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.