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Symlin

Symlin

CLINICAL PHARMACOLOGY

Amylin Physiology

Amylin is co-located with insulin in secretory granules and co-secreted with insulin by pancreatic beta cells in response to food intake. Amylin and insulin show similar fasting and postprandial patterns in healthy individuals (Figure 1).

Figure 1: Secretion Profile of Amylin and Insulin in Healthy Adults

Secretion Profile of Amylin and Insulin in Healthy Adults - illustration

Amylin affects the rate of postprandial glucose appearance through a variety of mechanisms. Amylin slows gastric emptying (i.e., the rate at which food is released from the stomach to the small intestine) without altering the overall absorption of nutrients. In addition, amylin suppresses glucagon secretion (not normalized by insulin alone), which leads to suppression of endogenous glucose output from the liver. Amylin also regulates food intake due to centrally-mediated modulation of appetite.

In patients with insulin-using type 2 or type 1 diabetes, the pancreatic beta cells are dysfunctional or damaged, resulting in reduced secretion of both insulin and amylin in response to food.

Mechanism of Action

SYMLIN (pramlintide acetate injection) , by acting as an amylinomimetic agent, has the following effects: 1) modulation of gastric emptying; 2) prevention of the postprandial rise in plasma glucagon; and 3) satiety leading to decreased caloric intake and potential weight loss.

Gastric Emptying. The gastric-emptying rate is an important determinant of the postprandial rise in plasma glucose. SYMLIN (pramlintide acetate injection) slows the rate at which food is released from the stomach to the small intestine following a meal and, thus, it reduces the initial postprandial increase in plasma glucose. This effect lasts for approximately 3 hours following SYMLIN (pramlintide acetate injection) administration. SYMLIN (pramlintide acetate injection) does not alter the net absorption of ingested carbohydrate or other nutrients.

Postprandial Glucagon Secretion. In patients with diabetes, glucagon concentrations are abnormally elevated during the postprandial period, contributing to hyperglycemia. SYMLIN (pramlintide acetate injection) has been shown to decrease postprandial glucagon concentrations in insulin-using patients with diabetes.

Satiety. SYMLIN (pramlintide acetate injection) administered prior to a meal has been shown to reduce total caloric intake. This effect appears to be independent of the nausea that can accompany SYMLIN (pramlintide acetate injection) treatment.

Pharmacokinetics

Absorption. The absolute bioavailability of a single SC dose of SYMLIN (pramlintide acetate injection) is approximately 30 to 40%. Subcutaneous administration of different doses of SYMLIN (pramlintide acetate injection) into the abdominal area or thigh of healthy subjects resulted in dose-proportionate maximum plasma concentrations (Cmax) and overall exposure (expressed as area under the plasma concentration curve or (AUC)) (Table 1).

Table 1: Mean Pharmacokinetic Parameters Following Administration of Single SC Doses of SYMLIN (pramlintide acetate injection)

SC Dose (mcg) AUC (0-∞) (pmol*min/L) Cmax (pmol/L) Tmax (min) Elimination t½ (min)
30 3750 39 21 55
60 6778 79 20 49
90 8507 102 19 51
120 11970 147 21 48

Injection of SYMLIN (pramlintide acetate injection) into the arm showed higher exposure with greater variability, compared with exposure after injection of SYMLIN (pramlintide acetate injection) into the abdominal area or thigh.

There was no strong correlation between the degree of adiposity as assessed by BMI or skin fold thickness measurements and relative bioavailability. Injections administered with 6.0-mm and 12.7-mm needles yielded similar bioavailability.

Distribution. SYMLIN (pramlintide acetate injection) does not extensively bind to blood cells or albumin (approximately 40% of the drug is unbound in plasma), and thus SYMLIN (pramlintide acetate injection) 's pharmacokinetics should be insensitive to changes in binding sites.

Metabolism and Elimination. In healthy subjects, the half-life of SYMLIN (pramlintide acetate injection) is approximately 48 minutes. SYMLIN (pramlintide acetate injection) is metabolized primarily by the kidneys. Des-lys1 pramlintide (2-37 pramlintide), the primary metabolite, has a similar half-life and is biologically active both in vitro and in vivo in rats. AUC values are relatively constant with repeat dosing, indicating no bioaccumulation.

Special Populations.

Renal Insufficiency: Patients with moderate or severe renal impairment (ClCr >20 to ≤ 50 mL/min) did not show increased SYMLIN (pramlintide acetate injection) exposure or reduced SYMLIN (pramlintide acetate injection) clearance, compared to subjects with normal renal function. No studies have been done in dialysis patients.

Hepatic Insufficiency: Pharmacokinetic studies have not been conducted in patients with hepatic insufficiency. However, based on the large degree of renal metabolism (see Metabolism and Elimination), hepatic dysfunction is not expected to affect blood concentrations of SYMLIN (pramlintide acetate injection) .

Geriatric: Pharmacokinetic studies have not been conducted in the geriatric population. SYMLIN (pramlintide acetate injection) should only be used in patients known to fully understand and adhere to proper insulin adjustments and glucose monitoring. No consistent age-related differences in the activity of SYMLIN (pramlintide acetate injection) have been observed in the geriatric population (n=539 for patients 65 years of age or older in the clinical trials).

Pediatric: SYMLIN (pramlintide acetate injection) has not been evaluated in the pediatric population.

Gender: No study has been conducted to evaluate possible gender effects on SYMLIN (pramlintide acetate injection) pharmacokinetics. However, no consistent gender-related differences in the activity of SYMLIN (pramlintide acetate injection) have been observed in the clinical trials (n=2799 for male and n=2085 for female).

Race/Ethnicity: No study has been conducted to evaluate the effect of ethnicity on SYMLIN (pramlintide acetate injection) pharmacokinetics. However, no consistent differences in the activity of SYMLIN (pramlintide acetate injection) have been observed among patients of differing race/ethnicity in the clinical trials (n=4257 for white, n=229 for black, n=337 for Hispanic, and n=61 for other ethnic origins).

Drug Interactions: The effect of SYMLIN (pramlintide acetate injection) (120 mcg) on acetaminophen (1000 mg) pharmacokinetics as a marker of gastric-emptying was evaluated in patients with type 2 diabetes (n=24). SYMLIN (pramlintide acetate injection) did not significantly alter the AUC of acetaminophen. However, SYMLIN (pramlintide acetate injection) decreased acetaminophen Cmax (about 29% with simultaneous co-administration) and increased the time to maximum plasma concentration or tmax (ranging from 48 to 72 minutes) dependent on the time of acetaminophen administration relative to SYMLIN (pramlintide acetate injection) injection. SYMLIN (pramlintide acetate injection) did not significantly affect acetaminophen tmax when acetaminophen was administered 1 to 2 hours before SYMLIN (pramlintide acetate injection) injection. However, the tmax of acetaminophen was significantly increased when acetaminophen was administered simultaneously with or up to 2 hours following SYMLIN injection (see PRECAUTIONS: DRUG INTERACTIONS).

Pharmacodynamics

In clinical studies in patients with insulin-using type 2 and type 1 diabetes, SYMLIN (pramlintide acetate injection) administration resulted in a reduction in mean postprandial glucose concentrations, reduced glucose fluctuations, and reduced food intake. SYMLIN (pramlintide acetate injection) doses differ for insulin-using type 2 and type 1 patients (see DOSAGE AND ADMINISTRATION).

Reduction in Postprandial Glucose Concentrations. SYMLIN (pramlintide acetate injection) administered subcutaneously immediately prior to a meal reduced plasma glucose concentrations following the meal when used with regular insulin or rapid-acting insulin analogs (Figure 2). This reduction in postprandial glucose decreased the amount of short-acting insulin required and limited glucose fluctuations based upon 24-hour glucose monitoring. When rapid-acting analog insulins were used, plasma glucose concentrations tended to rise during the interval between 150 minutes following SYMLIN injection and the next meal (see DOSAGE AND ADMINISTRATION).

Figure 2: Postprandial Plasma Glucose Profiles in Patients With Type 2 and Type 1 Diabetes Receiving SYMLIN (pramlintide acetate injection) and/or Insulin

Postprandial Plasma Glucose Profiles in Patients With Type 2 and Type 1 Diabetes Receiving SYMLIN and/or Insulin - illustration

Reduced Food Intake. A single, subcutaneous dose of SYMLIN (pramlintide acetate injection) 120 mcg (type 2) or 30 mcg (type 1) administered 1 hour prior to an unlimited buffet meal was associated with reductions in total caloric intake (placebo-subtracted mean changes of ~23% and 21%, respectively), which occurred without decreases in meal duration.

Clinical Studies

A total of 5325 patients and healthy volunteers received SYMLIN (pramlintide acetate injection) in clinical studies. This includes 1688 with type 2 diabetes and 2375 with type 1 diabetes in short- and long-term controlled clinical trials, long-term uncontrolled clinical trials, and an open-label study in the clinical practice setting.

Clinical Studies in Type 2 Diabetes

The efficacy of a range of SYMLIN (pramlintide acetate injection) doses was evaluated in several placebo-controlled and open-label clinical trials in insulin-using patients with type 2 diabetes. Based on results obtained in these studies, the recommended dose of SYMLIN (pramlintide acetate injection) for patients with insulin-using type 2 diabetes is 120 mcg administered immediately prior to major meals.

Two, long-term (26 to 52 week), randomized, double-blind, placebo-controlled studies of SYMLIN (pramlintide acetate injection) were conducted in patients with type 2 diabetes using fixed dose insulin to isolate the SYMLIN (pramlintide acetate injection) effect. Demographic and baseline characteristics for the 871 SYMLIN (pramlintide acetate injection) -treated patients are as follows: mean baseline HbA1c ranged from 9.0 to 9.4%, mean age was 56.4 to 59.1 years, mean duration of diabetes ranged from 11.5 to 14.4 years, and mean BMI ranged from 30.1 to 34.4 kg/m2. In both of these studies, SYMLIN (pramlintide acetate injection) or placebo was added to the participants' existing diabetes therapies, which included insulin with or without a sulfonylurea agent and/or metformin.

Table 2 summarizes the composite results across both studies for patients assigned to the 120-mcg dose after 6 months of treatment.

Table 2: Mean (SE) Change in HbA1c, Weight, and Insulin at 6 Months in the Double-Blind, Placebo-Controlled Studies in Patients With Insulin-using Type 2 Diabetes

Variable Placebo SYMLIN
(120 mcg)
Baseline HbA1c (%) 9.3 (0.08) 9.1 (0.06)
Change in HbA1c at 6 Months Relative to Baseline (%) -0.17 (0.07) -0.57 (0.06)*
Placebo-Subtracted HbA1c Change at 6 Months (%) NA -0.40 (0.09)*
Baseline Weight (kg) 91.3 (1.2) 92.5 (1.2)
Change in Weight at 6 Months Relative to Baseline (kg) +0.2 (0.2) -1.5 (0.2)*
Placebo-Subtracted Weight Change at 6 Months (kg) NA -1.7 (0.3)*
Percent Change in Insulin Doses at 6 Months: Rapid/Short-Acting +6.5 (2.7) -3.0 (1.6)*
Percent Change in Insulin Doses at 6 Months: Long-Acting +5.2 (1.4) -0.2 (1.3)*
* Statistically significant reduction compared with placebo (p-value < 0.05).

In a cohort of 145 patients who completed two years of SYMLIN (pramlintide acetate injection) treatment the baseline subtracted HbA1c and weight reductions were: -0.40% and -0.36 kg, respectively.

Open-Label Study in the Clinical Practice Setting. An open-label study of SYMLIN (pramlintide acetate injection) was conducted at the recommended dose of 120 mcg in 166 patients with insulin-using type 2 diabetes who were unable to achieve glycemic targets using insulin alone. A flexible-dose insulin regimen was employed in these patients (see DOSAGE AND ADMINISTRATION). In this study, patients adjusted their insulin regimen based on pre-and post-meal glucose monitoring. At baseline, mean HbA1c was 8.3%, mean age was 54.4 years, mean duration of diabetes was 13.3 years, and mean BMI was 38.6 kg/m2. SYMLIN (pramlintide acetate injection) was administered with major meals. SYMLIN (pramlintide acetate injection) plus insulin treatment for 6 months resulted in a baseline-subtracted mean HbA1c reduction of -0.56 ± 0.15 % and a baseline-subtracted mean weight reduction of -2.76 ± 0.34 kg. These changes were accomplished with reductions in doses of total, short-acting, and long-acting insulin (-6.4 ± 2.66, -10.3 ± 4.84, and -4.20 ± 2.42 %, respectively).

Clinical Studies in Type 1 Diabetes

The efficacy of a range of SYMLIN (pramlintide acetate injection) doses was evaluated in several placebo-controlled and open-label clinical trials conducted in patients with type 1 diabetes. Based on results obtained in these studies, the recommended dose of SYMLIN (pramlintide acetate injection) for patients with type 1 diabetes is 30 mcg or 60 mcg administered immediately prior to major meals.

Three, long-term (26 to 52 week), randomized, double-blind, placebo-controlled studies of SYMLIN (pramlintide acetate injection) were conducted in patients with type 1 diabetes (N=1717). Two of these studies allowed only minimal insulin adjustments in order to isolate the SYMLIN (pramlintide acetate injection) effect; in the third study, insulin adjustments were made according to standard medical practice. Demographic and baseline characteristics for the 1179 SYMLIN (pramlintide acetate injection) -treated patients were as follows: mean baseline HbA1c range was 8.7 to 9.0%, mean age range was 37.3 to 41.9 years, mean duration of diabetes range was 15.5 to 19.2 years, and mean BMI range was 25.0 to 26.8 kg/m2. SYMLIN (pramlintide acetate injection) or placebo was added to existing insulin therapies.

Table 3 summarizes the composite results across these studies for patients assigned to the 30 or 60 mcg dose after 6 months of treatment.

Table 3: Mean (SE) Change in HbA1c, Weight, and Insulin at 6 Months in the Double-Blind, Placebo-Controlled Studies in Patients With Type 1 Diabetes

Variable Placebo SYMLIN
(30 or 60 mcg)
Baseline HbA1c (%) 9.0 (0.06) 8.9 (0.04)
Change in HbA1c at 6 Months Relative to Baseline (%) -0.10 (0.05) -0.43 (0.04)*
Placebo-Subtracted HbA1c Change at 6 Months (%) NA -0.33 (0.06)*
Baseline Weight (kg) 75.1 (0.6) 76.1 (0.5)
Change in Weight at 6 Months Relative to Baseline (kg) +0.6 (0.1) -1.1 (0.1)*
Placebo-Subtracted Weight Change at 6 Months (kg) NA -1.7 (0.1)*
Percent Change in Insulin Doses at 6 Months: Rapid/Short-Acting +1.7 (3.3) -3.6 (2.9)
Percent Change in Insulin Doses at 6 Months: Long-Acting +2.5 (1.9) +1.9 (1.3)
* Statistically significant reduction compared with placebo (p-value < 0.05).

In a cohort of 73 patients who completed two years of SYMLIN (pramlintide acetate injection) treatment the baseline subtracted HbA1c and weight changes were: -0.35% and 0.60 kg, respectively.

SYMLIN (pramlintide acetate injection) Dose-Titration Trial. A dose-titration study of SYMLIN (pramlintide acetate injection) was conducted in patients with type 1 diabetes. Patients with relatively good baseline glycemic control (mean HbA1c = 8.1%) were randomized to receive either insulin plus placebo or insulin plus SYMLIN (pramlintide acetate injection) . Other baseline and demographics characteristics were: mean age of 41 years, mean duration of diabetes of 20 years, mean BMI of 28 kg/m2. SYMLIN (pramlintide acetate injection) was initiated at a dose of 15 mcg and titrated upward at weekly intervals by 15-mcg increments to doses of 30 mcg or 60 mcg, based on whether patients experienced nausea. Once a tolerated dose of either 30 mcg or 60 mcg was reached, the SYMLIN (pramlintide acetate injection) dose was maintained for the remainder of the study (SYMLIN (pramlintide acetate injection) was administered before major meals). During SYMLIN (pramlintide acetate injection) titration, the insulin dose (mostly the short/rapid acting insulin) was reduced by 30-50% in order to reduce the occurrence of hypoglycemia. Once a tolerated SYMLIN (pramlintide acetate injection) dose was reached, insulin dose adjustments were made according to standard clinical practice, based on pre- and post-meal blood glucose monitoring. By 6 months of treatment, patients treated with SYMLIN (pramlintide acetate injection) and insulin and patients treated with insulin and placebo had equivalent reductions in mean HbA1c (-0.47 ± 0.07 % vs. -0.49 ± 0.07 %, respectively); patients on SYMLIN (pramlintide acetate injection) lost weight (-1.33 ± 0.31 kg relative to baseline and -2.6 kg relative to placebo plus insulin-treated patients). SYMLIN (pramlintide acetate injection) -treated patients used less total insulin (-11.7% relative to baseline) and less short/rapid-acting insulin (-22.8%) relative to baseline.

Open-Label Study in the Clinical Practice Setting. An open-label study of SYMLIN (pramlintide acetate injection) was conducted in patients with type 1 diabetes who were unable to achieve glycemic targets using insulin alone. A flexible-dose insulin regimen was employed in these patients after SYMLIN titration was completed (see DOSAGE AND ADMINISTRATION). In this study, patients adjusted their insulin regimen based on pre-and post-meal glucose monitoring. At baseline, mean HbA1c was 8.0%, mean age was 42.7 years, mean duration of diabetes was 21.2 years, and mean BMI was 28.6 kg/m2. SYMLIN (pramlintide acetate injection) daily dosage was 30 mcg or 60 mcg with major meals.

SYMLIN (pramlintide acetate injection) plus insulin reduced HbA1c and body weight from baseline at 6 months by a mean of 0.18% and 3.0 kg, respectively. These changes in glycemic control and body weight were achieved with reductions in doses of total, short-acting, and long-acting insulin (-12.0 ± 1.36, -21.7 ± 2.81, and -0.4 ± 1.59 %, respectively).

Last reviewed on RxList: 4/9/2008
This monograph has been modified to include the generic and brand name in many instances.

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