Acarbose

ACARBOSE- acarbose tablet
Aphena Pharma Solutions — Tennessee, LLC

DESCRIPTION

Acarbose is an oral alpha-glucosidase inhibitor for use in the management of type 2 diabetes mellitus. Acarbose is an oligosaccharide which is obtained from fermentation processes of a microorganism, Actinoplanes utahensis, and is chemically known as O-4,6-dideoxy- 4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]-α-D-glucopyranosyl-(1 → 4)-O-α-D-glucopyranosyl-(1 → 4)-D-glucose. It is a white to off-white powder with a molecular weight of 645.6. Acarbose is soluble in water and has a pKa of 5.1. Its empirical formula is C25 H43 NO18 and its chemical structure is as follows:

Chemical Structure
(click image for full-size original)

Acarbose tablets are available as 100 mg tablets for oral use. The inactive ingredients are starch, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide.

CLINICAL PHARMACOLOGY

Acarbose is a complex oligosaccharide that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, acarbose reduces levels of glycosylated hemoglobin in patients with type 2 diabetes mellitus. Systemic non-enzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.

Mechanism of Action

In contrast to sulfonylureas, acarbose does not enhance insulin secretion. The antihyperglycemic action of acarbose results from a competitive, reversible inhibition of pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in a delayed glucose absorption and a lowering of postprandial hyperglycemia.

Because its mechanism of action is different, the effect of acarbose to enhance glycemic control is additive to that of sulfonylureas, insulin or metformin when used in combination. In addition, acarbose diminishes the insulinotropic and weight-increasing effects of sulfonylureas.

Acarbose has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.

Pharmacokinetics

Absorption

In a study of 6 healthy men, less than 2% of an oral dose of acarbose was absorbed as active drug, while approximately 35% of total radioactivity from a 14 C-labeled oral dose was absorbed. An average of 51% of an oral dose was excreted in the feces as unabsorbed drug-related radioactivity within 96 hours of ingestion. Because acarbose acts locally within the gastrointestinal tract, this low systemic bioavailability of parent compound is therapeutically desired. Following oral dosing of healthy volunteers with 14 C-labeled acarbose, peak plasma concentrations of radioactivity were attained 14–24 hours after dosing, while peak plasma concentrations of active drug were attained at approximately 1 hour. The delayed absorption of acarbose-related radioactivity reflects the absorption of metabolites that may be formed by either intestinal bacteria or intestinal enzymatic hydrolysis.

Metabolism

Acarbose is metabolized exclusively within the gastrointestinal tract, principally by intestinal bacteria, but also by digestive enzymes. A fraction of these metabolites (approximately 34% of the dose) was absorbed and subsequently excreted in the urine. At least 13 metabolites have been separated chromatographically from urine specimens. The major metabolites have been identified as 4-methylpyrogallol derivatives (that is, sulfate, methyl, and glucuronide conjugates). One metabolite (formed by cleavage of a glucose molecule from acarbose) also has alpha-glucosidase inhibitory activity. This metabolite, together with the parent compound, recovered from the urine, accounts for less than 2% of the total administered dose.

Excretion

The fraction of acarbose that is absorbed as intact drug is almost completely excreted by the kidneys. When acarbose was given intravenously, 89% of the dose was recovered in the urine as active drug within 48 hours. In contrast, less than 2% of an oral dose was recovered in the urine as active (that is, parent compound and active metabolite) drug. This is consistent with the low bioavailability of the parent drug. The plasma elimination half-life of acarbose activity is approximately 2 hours in healthy volunteers. Consequently, drug accumulation does not occur with three times a day (t.i.d.) oral dosing.

Special Populations

The mean steady-state area under the curve (AUC) and maximum concentrations of acarbose were approximately 1.5 times higher in elderly compared to young volunteers; however, these differences were not statistically significant. Patients with severe renal impairment (Clcr < 25 mL/min/1.73m2) attained about 5 times higher peak plasma concentrations of acarbose and 6 times larger AUCs than volunteers with normal renal function. No studies of acarbose pharmacokinetic parameters according to race have been performed. In U.S. controlled clinical studies of acarbose in patients with type 2 diabetes mellitus, reductions in glycosylated hemoglobin levels were similar in Caucasians (n=478) and African-Americans (n=167), with a trend toward a better response in Latinos (n=132).

Drug-Drug Interactions

Studies in healthy volunteers have shown that Acarbose has no effect on either the pharmacokinetics or pharmacodynamics of nifedipine, propranolol, or ranitidine. acarbose did not interfere with the absorption or disposition of the sulfonylurea glyburide in diabetic patients. Acarbose may affect digoxin bioavailability and may require dose adjustment of digoxin by 16% (90% confidence interval: 8-23%), decrease mean Cmax of digoxin by 26% (90% confidence interval: 16–34%) and decreases mean trough concentrations of digoxin by 9% (90% confidence limit: 19% decrease to 2% increase). (See PRECAUTIONS, Drug Interactions.)

The amount of metformin absorbed while taking acarbose was bioequivalent to the amount absorbed when taking placebo, as indicated by the plasma AUC values. However, the peak plasma level of metformin was reduced by approximately 20% when taking Acarbose due to a slight delay in the absorption of metformin. There is little if any clinically significant interaction between acarbose and metformin.

CLINICAL TRIALS

Clinical Experience from Dose Finding Studies in Type 2 Diabetes Mellitus Patients on Dietary Treatment Only: Results from six controlled, fixed-dose, monotherapy studies of acarbose in the treatment of type 2 diabetes mellitus, involving 769 acarbose-treated patients, were combined and a weighted average of the difference from placebo in the mean change from baseline in glycosylated hemoglobin (HbA1c) was calculated for each dose level as presented below:

Table 1 Mean Placebo-Subtracted Change in HbA1c in Fixed-Dose Monotherapy Studies
*
Acarbose was statistically significantly different from placebo at all doses. Although there were no statistically significant differences among the mean results for doses ranging from 50 to 300 mg t.i.d., some patients may derive benefit by increasing the dosage from 50 to 100 mg t.i.d.
Although studies utilized a maximum dose of 200 or 300 mg t.i.d., the maximum recommended dose for patients ≤ 60 kg is 50 mg t.i.d.; the maximum recommended dose for patients > 60 kg is 100 mg t.i.d.

Dose of acarbose **

N

Change in HbA1c

%

p-Value
25 mg t.i.d.

110

-0.44

0.0307
50 mg t.i.d.

131

-0.77

0.0001
100 mg t.i.d.

244

-0.74

0.0001
200 mg t.i.d.

231

-0.86

0.0001
300 mg t.i.d.

53

-1.00

0.0001

Results from these six fixed-dose, monotherapy studies were also combined to derive a weighted average of the difference from placebo in mean change from baseline for one-hour postprandial plasma glucose levels as shown in the following figure:

Figure 1
(click image for full-size original)

* Acarbose was statistically significantly different from placebo at all doses with respect to effect on one-hour postprandial plasma glucose.

**The 300 mg t.i.d. acarbose regimen was superior to lower doses, but there were no statistically significant differences from 50 to 200 mg t.i.d.

Clinical Experience in Type 2 Diabetes Mellitus Patients on Monotherapy, or in Combination with Sulfonylureas, Metformin or Insulin: acarbose was studied as monotherapy and as combination therapy to sulfonylurea, metformin, or insulin treatment. The treatment effects on HbA1c levels and one-hour postprandial glucose levels are summarized for four placebo-controlled, double-blind, randomized studies conducted in the United States in Tables 2 and 3, respectively. The placebo-subtracted treatment differences, which are summarized below, were statistically significant for both variables in all of these studies.

Study 1 (n=109) involved patients on background treatment with diet only. The mean effect of the addition of acarbose to diet therapy was a change in HbA1c of -0.78%, and an improvement of one-hour postprandial glucose of -74.4 mg/dL.

In Study 2 (n=137), the mean effect of the addition of acarbose to maximum sulfonylurea therapy was a change in HbA1c of -0.54%, and an improvement of one-hour postprandial glucose of -33.5 mg/dL.

In Study 3 (n=147), the mean effect of the addition of acarbose to maximum metformin therapy was a change in HbA1c of -0.65%, and an improvement of one-hour postprandial glucose of -34.3 mg/dL.

Study 4 (n=145) demonstrated that acarbose added to patients on background treatment with insulin resulted in a mean change in HbA1c of -0.69%, and an improvement of one-hour postprandial glucose of -36.0 mg/dL.

A one year study of acarbose as monotherapy or in combination with sulfonylurea, metformin or insulin treatment was conducted in Canada in which 316 patients were included in the primary efficacy analysis (Figure 2). In the diet, sulfonylurea and metformin groups, the mean decrease in HbA1c produced by the addition of acarbose was statistically significant at six months, and this effect was persistent at one year. In the acarbose-treated patients on insulin, there was a statistically significant reduction in HbA1c at six months, and a trend for a reduction at one year.

Table 2: Effect of Acarbose on HbA1c
*
HbA1c Normal Range: 4–6%
After four months treatment in Study 1, and six months in Studies 2, 3, and 4
SFU, sulfonylurea, maximum dose
§
Although studies utilized a maximum dose of up to 300 mg t.i.d., the maximum recommended dose for patients ≤ 60 kg is 50 mg t.i.d.; the maximum recommended dose for patients > 60 kg is 100 mg t.i.d.
Metformin dosed at 2000 mg/day or 2500 mg/day
#
Mean dose of insulin 61 U/day
Þ
Results are adjusted to a common baseline of 8.33%

HbA1c (%) *

Study

Treatment

Mean

Mean change

Treatment

p-Value

Baseline

from baseline

Difference

1

Placebo Plus Diet

8.67

+0.33

acarbose 100 mg t.i.d.

8.69

-0.45

-0.78

0.0001

Plus Diet

2

Placebo Plus SFU

9.56

+0.24

acarbose 50–300§ mg t.i.d.

9.64

-0.30

-0.54

0.0096

Plus SFUc

3

Placebo Plus Metformin

8.17

+0.08 g

acarbose 50–100 mg t.i.d.

8.46

-0.57 g

-0.65

0.0001

Plus Metformin #

4

Placebo Plus Insulin Þ

8.69

+0.11

acarbose 50–100 mg t.i.d.

8.77

-0.58

-0.69

0.0001

Plus Insulinf
Table 3: Effect of Acarbose on Postprandial Glucose
*
After four months treatment in Study 1, and six months in Studies 2, 3, and 4
SFU, sulfonylurea, maximum dose
Although studies utilized a maximum dose of up to 300 mg t.i.d., the maximum recommended dose for patients ≤ 60 kg is 50 mg t.i.d.; the maximum recommended dose for patients > 60 kg is 100 mg t.i.d.
§
Metformin dosed at 2000 mg/day or 2500 mg/day
Results are adjusted to a common baseline of 273 mg/dL
#
Mean dose of insulin 61 U/day

One-Hour Postprandial Glucose (mg/dL)

Study

Treatment

Mean

Mean change

Treatment

p-Value

Baseline

from baseline *

Difference

1

Placebo Plus Diet

297.1

+31.8

acarbose 100 mg t.i.d.

299.1

-42.6

-74.4

0.0001

Plus Diet

2

Placebo Plus SFU

308.6

+6.2

acarbose 50–300 mg t.i.d.

311.1

-27.3

-33.5

0.0017

Plus SFU

3

Placebo Plus Metformin §

263.9

+3.3

acarbose 50–100 mg t.i.d.

283.0

-31.0

-34.3

0.0001

Plus Metformin §

4

Placebo Plus Insulin #

279.2

+8.0

acarbose 50–100 mg t.i.d.

277.8

-28.0

-36.0

0.0178

Plus Insulin #

Figure 2

Figure 2
(click image for full-size original)

Figure 2: Effects of Acarbose ( ■ ) and Placebo ( ● ) on mean change in HbA1c levels from baseline throughout a one-year study in patients with type 2 diabetes mellitus when used in combination with: (A) diet alone; (B) sulfonylurea; (C) metformin; or (D) insulin. Treatment differences at 6 and 12 months were tested: * p < 0.01; # p = 0.077.

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