Nateglinide (Page 3 of 7)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nateglinide lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K + ATP ) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.

12.2 Pharmacodynamics

Nateglinide stimulates pancreatic insulin secretion within 20 minutes of oral administration. When nateglinide is dosed before meals, the peak rise in plasma insulin occurs approximately 1 hour after dosing and falls to baseline by 4 hours after dosing.

12.3 Pharmacokinetics

In patients with Type 2 diabetes, multiple dose administration of nateglinide over the dosage range of 60 mg to 240 mg shows linear pharmacokinetics for both area under the curve (AUC) and C max . In patients with Type 2 diabetes, there is no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days.

Absorption
Absolute bioavailability of nateglinide is approximately 73%. Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to a meal. Following oral administration immediately prior to a meal, the mean peak plasma nateglinide concentrations (C max ) generally occur within 1 hour (T max ) after dosing. T max is independent of dose.

The pharmacokinetics of nateglinide are not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels are significantly reduced when nateglinide is administered 10 minutes prior to a liquid meal as compared to solid meal. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in C max and a delay in time to peak plasma concentration (T max ).

Nateglinide did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.

Distribution
Following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 L in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent α 1 acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1 to 10 mcg/mL.

Elimination
In healthy volunteers and patients with type 2 diabetes mellitus, nateglinide plasma concentrations declined with an average elimination half-life of approximately 1.5 hours.

Metabolism
In vitro drug metabolism studies indicate that nateglinide is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%).

The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide.

Excretion
Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Eighty-three percent of the 14 C -nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14 C -nateglinide was excreted in the urine as parent compound.

Specific Populations
Renal Impairment
No pharmacokinetic data are available in subjects with mild renal impairment (CrCl 60 to 89 mL/min). Compared to healthy matched subjects, patients with type 2 diabetes mellitus and moderate and severe renal impairment (CrCl 15-50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and C max. Patients with type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure (C max decreased by 49%; not statistically significant). However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.

In a cohort of 8 patients with type 2 diabetes and end-stage renal disease (ESRD) (eGFR < 15 mL/min/1.73m 2) M1 metabolite accumulation up to 1.2 ng/mL occurred with a dosage of 90 mg once daily for 1 to 3 months. In another cohort of 8 patients with type 2 diabetes on hemodialysis, M1 concentration decreased after a single session of hemodialysis. Although the hypoglycemic activity of the M1 metabolite is approximately 5 times lower than nateglinide, metabolite accumulation may increase the hypoglycemic effect of the administered dose.

Hepatic Impairment
In patients with mild hepatic impairment, the mean increase in C max and AUC of nateglinide were 37% and 30% respectively, as compared to healthy matched control subjects. There is no data on pharmacokinetics of nateglinide in patients with moderate-to-severe hepatic impairment.

Gender
No clinically significant differences in nateglinide pharmacokinetics were observed between men and women.

Race
Results of a population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide.

Age
Age does not influence the pharmacokinetic properties of nateglinide.

Drug Interactions:
In vitro assessment of drug interactions
Nateglinide is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments.

In vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid, and tolbutamide in vitro. However, prudent evaluation of individual cases is warranted in the clinical setting.

In vivo assessment of drug interactions The effect of coadministered drugs on the pharmacokinetics of nateglinide and the effect of nateglinide on pharmacokinetics of coadministered drugs are shown in Tables 3 and 4. No clinically relevant change in pharmacokinetic parameters of either agent was reported when nateglinide was coadministered with glyburide, metformin, digoxin, warfarin, and diclofenac.

Table 3: Effect of Coadministered Drugs on Pharmacokinetics of Nateglinide
AM: after morning dose; PM: after evening dose; *after second dose; ↑: increase in the parameter; ↓: decrease in the parameter

Coadministered drug

Dosing regimen of coadministered drug

Dosing regimen of nateglinide

Change in C max

Change in AUC

Glyburide

10 mg once daily for 3 weeks

120 mg three times a day, single dose

8.78% ↓

3.53 % ↓

Metformin

500 mg three times a day for 3 weeks

120 mg three times a day, single dose

AM: 7.14% ↑

PM: 11.4% ↓

AM: 1.51% ↑

PM: 5.97% ↑

Digoxin

1 mg, single dose

120 mg three times a day, single dose

AM: 2.17% ↓

PM: 3.19% ↑

AM: 7.62% ↑

PM: 2.22% ↑

Warfarin

30 mg, single dose

120 mg three times a day for 4 days

2.65% ↑

3.72% ↓

Diclofenac

75 mg, single dose

120 mg twice daily, single dose

AM: 13.23% ↓

*PM: 3.76% ↑

AM: 2.2% ↓

*PM: 7.5% ↑

Table 4: Effect of Nateglinide on Pharmacokinetics of Coadministered Drugs
AM: after morning dose; PM: after evening dose; SD: single dose; ↑: increase in the parameter; ↓: decrease in the parameter

Coadministered drug

Dosing regimen of coadministered drug

Dosing regimen of nateglinide

Change in C max

Change in AUC

Glyburide

10 mg once daily for 3 weeks

120 mg three times a day, single dose

3.18% ↓

7.34% ↓

Metformin

500 mg three times a day for 3 weeks

120 mg three times a day, single dose

AM: 10.7% ↑

PM: 0.40% ↑

AM: 13.3% ↑

PM: 2.27% ↓

Digoxin

1 mg, single dose

120 mg three times a day, single dose

5.41% ↓

6.58 % ↑

Warfarin

30 mg, single dose

120 mg three times a day for 4 days

R-warfarin: 1.03% ↓

S-warfarin: 0.85% ↓

R-warfarin: 0.74% ↑

S-warfarin: 7.23% ↑

Diclofenac

75 mg, single dose

120 mg twice daily, single dose

2.19% ↑

7.97% ↑

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