April 25, 2017
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Starlix

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Starlix Tablet




CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

STARLIX stimulates pancreatic insulin secretion within 20 minutes of oral administration. When STARLIX 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.

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 AUC and Cmax. 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 (Cmax) generally occur within 1 hour (Tmax) after dosing. Tmax 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 STARLIX 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 Cmax and a delay in time to peak plasma concentration (Tmax).

STARLIX 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 α1 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 STARLIX 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 14C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14C-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 Cmax. Patients with type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure (Cmax decreased by 49%; not statistically significant). However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.

Hepatic Impairment

In patients with mild hepatic impairment, the mean increase in Cmax and AUC of nateglinide were 37% and 30 % respectively, as compared to healthy matched control subjects. There is no data on pharmacokinetics of STARLIX 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

STARLIX 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

Coadministered drug Dosing regimen of coadministered drug Dosing regimen of nateglinide Change in Cmax 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% ↑
AM: after morning dose; PM: after evening dose; * after second dose; ↑ increase in the parameter; ↓:decrease in the parameter

Table 4: Effect of Nateglinide on Pharmacokinetics of Coadministered Drugs

Coadministered drug Dosing regimen of coadministered drug Dosing regimen of nateglinide Change in Cmax 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% ↑
AM: after morning dose; PM: after evening dose; SD: single dose; ↑: increase in the parameter; ↓: decrease in the parameter

Clinical Studies

Monotherapy

In a 24-week, double-blind, placebo-controlled study, patients with type 2 diabetes were randomized to receive either STARLIX (60 mg or 120 mg three times daily before meals) or placebo. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least 2 months before randomization.

At Week 24, treatment with STARLIX before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 5). The reductions in HbA1C and FPG were similar for patient’s naïve to, and those previously exposed to, antidiabetic medications.

Table 5: Endpoint Results for a 24-week, Fixed Dose Study of STARLIX Monotherapy

  Placebo STARLIX 60 mg three times daily before meals STARLIX 120 mg three times daily before meals
HbA1C (%) N=168 N=167 N=168
Baseline (mean) 8.0 7.9 8.1
Change from baseline (mean) +0.2 -0.3 -0.5
Difference from placebo (mean)   -0.5 a -0.7 a
FPG (mg/dL) N=172 N=171 N=169
Baseline (mean) 167.9 161.0 166.5
Change from baseline (mean) +9.1 +0.4 -4.5
Difference from placebo (mean)   -8.7 a -13.6a
a p-value ≤ 0.004

Monotherapy Compared To Glyburide

In a 24-week, double-blind, active-controlled trial, patients with type 2 diabetes who had been on a sulfonylurea for 3 or more months and who had a baseline HbA1C greater than or equal to 6.5% were randomized to receive STARLIX (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to STARLIX had significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.

Table 6: Endpoint Results for a 24-week Study of STARLIX Monotherapy Compared to Glyburide

  Glyburide 10 mg Once daily STARLIX 60 mg three times daily before meals STARLIX 120 mg three times daily before meals
HbA1C (%) N=183 N=178 N=179
Baseline (mean) 7.8 8.0 7.9
Change from baseline (mean) 0.3 1.3 1.1
Difference from placebo (mean)   1.0 a 0.9a
FPG (mg/dL) N=184 N=182 N=180
Baseline (mean) 9.44 9.67 9.61
Change from baseline (mean) 0.19 3.06 2.84
Difference from placebo (mean)   2.87 a 2.66a
a p-value <0.001

Monotherapy And In Combination With Metformin

In a 24-week, double-blind, active- and placebo-controlled study, patients with type 2 diabetes were randomized to receive either STARLIX alone (120 mg three times daily before meals), metformin alone (500 mg three times daily), a combination of STARLIX 120 mg (three times daily before meals) and metformin (500 mg three times daily), or placebo. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least 2 months before randomization.

At Week 24, statistically significant reductions in mean HbA1c and FPG were observed with metformin monotherapy compared to STARLIX monotherapy, and the combination of STARLIX and metformin compared to either STARLIX or metformin monotherapy (see Table 7).

Compared to placebo, STARLIX monotherapy was associated with a statistically significant increase in mean body weight, while no significant change in body weight was observed with metformin monotherapy or combination of STARLIX and metformin therapy (see Table 7). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the STARLIX monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 7).

Table 7: Endpoint results for a 24-week study of STARLIX Monotherapy and Combination with Metformin

  Placebo STARLIX 120 mg three times daily before meals Metformin 500 mg three times daily STARLIX 120 mg before meals plus Metformin*
HbA1C (%)
All
N=160 N=171 N=172 N=162
Baseline (mean) 8.3 8.3 8.4 8.4
Change from baseline (mean) +0.4 -0.4bc -0.8c -1.5
Difference from placebo   -0.8a -1.2a -1.9a
Naїve N=98 N=99 N=98 N=81
Baseline (mean) 8.2 8.1 8.3 8.2
Change from baseline (mean) +0.3 -0.7c -0.8c -1.6
Difference from placebo   -1.0 a -1.1a -1.9 a
Non-Naїve N=62 N=72 N=74 N=81
Baseline (mean) 8.3 8.5 8.7 8.7
Change from baseline (mean) +0.6 +0.004bc -0.8c -1.4
Difference from placebo   -0.6 a -1.4 a -2.0 a
FPG (mg/dL)
All
N=166 N=173 N=174 N=167
Baseline (mean) 194.0 196.5 196.0 197.7
Change from baseline (mean) +8.0 -13.1bc -30.0c -44.9
Difference from placebo   -21.1 a -38.0 a -52.9 a
a p-value ≤ 0.05 vs. placebo
b p-value ≤ 0.03 vs. metformin
c p-value ≤ 0.05 vs. combination
* Metformin was administered three times daily

In another 24-week, double-blind, placebo-controlled trial, patients with type 2 diabetes with HbA1C greater than or equal to 6.8% after treatment with metformin (greater than or equal to 1500 mg daily for at least 1 month) were first entered into a four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive either STARLIX (60 mg or 120 mg three times daily before meals) or placebo as add-on to metformin. At the end of treatment, STARLIX 60 mg and 120 mg three times daily resulted in a statistically significantly greater reductions in HbA1C compared to placebo when added to metformin (-0.4% and -0.6% for STARLIX 60 mg and STARLIX 120 mg plus metformin, respectively).

Table 8: Endpoint Results for a 24-week Study of STARLIX Monotherapy as Add-on to Metformin

  Placebo + metformin STARLIX 60 mg
+
metformin
STARLIX 120 mg
+
metformin
HbA1C (%) N=150 N=152 N=154
Baseline (mean) 8.2 8.0 8.2
Change from baseline (mean) 0.01 -0.4 -0.6
Difference from placebo (mean)   -0.4 a -0.6 b
a p-value 0.003 vs. metformin
bp-value < 0.001 vs. metformin
All STARLIX/placebo taken three times daily before meals; all metformin 1000 mg twice daily.

Add-On Combination Therapy With Rosiglitazone

A 24-week, double blind, multicenter, placebo-controlled trial was performed in patients with type 2 diabetes not adequately controlled on rosiglitazone 8 mg daily. The addition of STARLIX (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1C compared to placebo as add-on to rosiglitazone. The mean change in weight from baseline was +3 kg for patients treated with STARLIX compared to +1 kg for patients treated with placebo when added to rosiglitazone.

Table 9: Endpoint Results for a 24-week Study of the Effect of Adding STARLIX or Placebo to Rosiglitazone

  Placebo + rosiglitazone 8 mg once daily STARLIX 120 mg before meals + rosiglitazone 8 mg once daily
HbA1C (%) N=191 N=194
Baseline (mean) 8.4 8.3
Change from baseline (mean) 0.03 -0.7
Difference from rosiglitazone (mean)   -0.7a
a p-value . 0.0001

Add-On Combination Therapy With Glyburide

In a 12-week study of patients with type 2 diabetes inadequately controlled on glyburide 10 mg once daily, the addition of STARLIX (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.

Table 10: Endpoint Results for a 12-week Study of the Effect of Adding STARLIX or Placebo to Glyburide

  Placebo + glyburide 10 mg once daily STARLIX 60 mg before meals + glyburide 10 mg once daily STARLIX 120 mg before meals + glyburide 10 mg once daily
HbA1C (%) N=58 N=55 N=54
Baseline (mean) 8.7 8.7 8.7
Change from baseline (mean) 0.3 0.2 -0.02
Difference from glyburide (mean)   -0.1a -0.3b
Placebo or STARLIX given 10 minutes prior to breakfast, lunch, and dinner; glyburide given with the breakfast dose of STARLIX or placebo.
a p-value 0.6959
b p-value 0.1246

Last reviewed on RxList: 4/11/2017
This monograph has been modified to include the generic and brand name in many instances.

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