Exenatide

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Authored by: Rlweber 08:48, 16 April 2007 (PDT)


Exenatide Quick Reference
Exenatide
IUPAC Name
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
Chemical Information
Empirical Formula C184H282N50O60S
Molecular Weight 4186.6 Daltons
General Drug Information
Classification Incretin Mimetic; GLP-1 Analog; Antihyperglycemic Agents
Schedule Legend
How Supplied Solution for Injection 250mcg/ml (Pre-filled Pen)
Trade Names Byetta™
Pregnancy Category C
Breast Feeding It is unknown if exenatide is excreted into human breast milk.
Generic Availability Currently Unavailable
Patent Expiration Date May 24,2013; Jan 06,2017; Jan 07,2018; Jan 14,2020
Administration Information
Route(s) Subcutaneously into thigh, abdomen, or upper arm
Method(s) Administer within an hour prior to morning and evening meals.
Pharmacokinetic Information
Absorption F = Unknown; Comparable with subcutaneous administration into the arm, abdomen or thigh.
Cmax = 211 pg/ml (after 10 mcg dose)
Tmax = ~2.1 hours
Distribution Vd = 28.3L
Metabolism Minimal sytemic metabolism; Eliminated by glomerular filtration with proteolytic degradation
Excretion t1/2 =2.4 hours
Urine (majority of dose); Cl=9.1 L/h

Contents

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Brand/Trade Names of Drug

Byetta™

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Generic Name of Drug

Exenatide (ex EN a tide) Exenatide Pronunciation Click Here


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Description

Exenatide is the first incretin mimetic approved for clinical use by the FDA.[1] It received its first FDA approval in April 2005.[2] It later received FDA approval (January 2007) for treatment of type II diabetes mellitus in conjunction with a thiazolidinedione with or without metformin.[2] Incretin memetics mimic the effects of endogenous incretin hormones.[1] Glucose-dependant insulinotropic polypeptides are gut hormones, and patients with type II diabetes mellitus often lack the glucose-lowering response to these polypeptides, accounting for the forceful insulin secretion from their pancreatic beta-cells after oral ingestion of glucose.[1] Exenatide was originally isolated from the salivary glands of the Heloderma suspectum lizard, and acts to enhance glucose-dependant insulin secretion, enhancement of glucose-dependant suppression of high glucagon secretion, slow gastric emptying, reduce food intake, restore first-phase insulin secretion and promote beta-cell proliferation.[1]


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Mechanism of action

Exenatide acts to enhance glucose-dependant insulin secretion following its release into the gut.[3]Its also works by promoting insulin release from pancreatic beta-cells in the presence of elevated glucose levels.[3] Its amino acid sequence partly overlaps the human GLP-1 sequence, allowing for the activation of GLP-1 receptor.[3] This activation allows for increased glucose-dependant insulin synthesis and insulin secretion from pancreatic beta-cells.[3] By reducing fasting and postprandial glucose levels, reducing food intake, and slowing gastric emptying, exenatide helps to control glucose levels.[3]

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Pharmacokinetics

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Absorption

The exenatide AUC increases proportionally over a dose range of 5 mcg-10 mcg, with a less than proportional increase in the Cmax over the same range.[3] There is similar exposure of exenatide regardless of site of administration.[3] Following a single dose of 10 mcg, the Cmax was 211pg/ml with an overall AUC of 1036 pgh/ml.[3]

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Distribution

The volume of distribution of exenatide is 28.3L (following a single dose).[3]

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Metabolism

Exenatide undergoes minimal systemic metabolism, with glomerular filtration and proteolytic degradation acting as the main mechanism for drug breakdown.[3]

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Excretion

The majority of exenatide is eliminated via the urine, with a clearance of 9.1L/hour.[3] The half-life of exenatide is 2.4 hours.[3]


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Special Population Pharmacokinetics

  • Renal insufficiency Patients with end-stage renal disease undergoing dialysis will experience a reduced exenatide clearance (0.9 L/hour vs. 9.1 L/hour).[3] Patients with mild to moderate renal impairment (CrCl:30-80 ml/min) will experience a mild reduced clearance, and will require no dosage adjustment.[3]
  • Hepatic insufficiency Since exenatide is mainly eliminated renally, hepatic insufficiency is not believed to alter the levels of exenatide.[3] No pharmacokinetic studies in patients with acute or chronic hepatic insufficiency have been performed.[3]
  • Hemodialysis Unknown. Patients with end-stage renal disease undergoing dialysis will experience a reduced exenatide clearance (0.9 L/hour vs. 9.1 L/hour).[3]
  • Geriatric Age does not affect the pharmacokinetic properties of exenatide (ages:22-73 years).[3]
  • Pediatric The pharmacokinetic properties of exenatide has not been studied in this population.[3]
  • Gender Gender does not affect the pharmacokinetic properties of exenatide.[3]
  • Race Race does not affect the pharmacokinetic properties of exenatide (in studies using Caucasian, African American and Hispanic patients.[3]


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Indications

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FDA Approved Indications

  • Diabetes Mellitus Type II (in conjunction with a sulfonylurea, a thiazolidinedione and/or metformin)

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Non-FDA Approved Indications

  • None


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Dosage

  • Diabetes Mellitus Type II
    • Starting Dose: 5mcg/dose subcutaneously twice a day.[3][2]
    • Titration Schedule: Can increase to 10mcg subcutaneously twice daily after one month.[3][2]
    • Maintenance Dose: Based on patient response. Can be increased to 10 mcg subcutaneously twice daily.[3][2]


  • Maximum Dosage Limits
    • Adults: 20 mcg subcutaneously/day.[3][2]
    • Elderly: 20 mcg subcutaneously/day.[3][2]
    • Adolescents and children >=10 years: Safety and efficacy if exenatide has not been established in this population.[3][2]
    • Children < 10 years: Safety and effiacy if exenatide has not been established in this population.[3][2]
  • Dosage Adjustment
    • Renal insufficiency: CrCl <30 ml/min: Use is not recommended.[3][2]
    • Hepatic insufficiency: Guidelines for dosage adjustments in hepatic impairment are not available.[3][2]
    • Hemodialysis: Unknown
    • Geriatric: Dose adjustments not needed in this population.[3][2]
    • Pediatric: Safety and efficacy if exenatide has not been established in this population
    • Gender: Dose adjustments not needed in different races.[3][2]


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Administration

  • Route: Subcutaneously.[3]
  • Method: Pre-filled pen for thigh, abdomen, or upper arm injection.[3] Pinch a fold of skin on the thigh, abdomen or upper arm, insert needle and release the skin.[3] Inject at a 90-degree angle over 2-4 seconds.[3]
  • Special considerations: Inject one hour prior to morning and evening meals.[3] Give doses at least 6 hours apart and DO NOT inject after meals.[3] Rotate injection sites. Always check product for discoloration and precipitation.[3]

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Monitoring Parameters

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Contraindications/Precautions

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Contraindications

  • Patients with known hypersensitivity to exenatide or any of its components.[3]
  • Diabetes Mellitus Type I.[3]
  • Diabetic Ketoacidosis.[3]


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Precautions

  • End-stage renal disease/severe renal impairment.[3]
  • Patients with severe gastrointestinal disease.[3]
  • Pregnancy/Breast-feeding.[3]


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Pregnancy indications

  • Pregnancy category: C
  • Teratogenicity: Exenatide has been associated with reduced fetal and neonatal growth in mice and skeletal effects in mice and rats (at a dose of 20 mcg/day).[3] There have been no well-controlled studies of exenatide use in pregnant women.[3] Exenatide should only be used during pregnancy if the benefits clearly outweigh and justify the risk to the fetus.[3]


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Breast-feeding indications

  • Secretion into breast milk: It is unknown if exenatide is excreted into human breast milk.[3] Although studies in lactating mice show that exenatide is present in low concentrations in milk (less than or equal to 2.5% of the concentration in maternal plasma after subcutaneous dosing), caution should be used when exenatide is to be used in a nursing woman.[3]

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Drug-Drug Interactions

Exenatide Drug/Drug Interaction Chart
Severity Level Click here to see Severity Level Legend Increased Effect/Toxicity Decreased Effect
4 None Known None Known
3 None Known None Known
2 Insulins[3] Can increase the risk of hypoglycemia Antidiabetic Medications[3] Can increase the risk of hypoglycemia Beta-blockers/Clonidine[3] Beta-blockers/Clonidine can cause hypoglycemia, prolong hypoglycemia and mask the signs/symptoms of hypoglycemia. Fluoxetine[4] Fluoxetine can enhance the effects of antidiabetic medications Mecasermin recombinant/Mecasermin rinfabate[5] Mecasermin recombinant/Mecasermin can lower blood glucose and cause hypoglycemia. MAOIs[6] MAOIs can stimulate insulin secretion and prolong hypoglycemia Corticosteroids[3] Can cause an increase in blood sugar and subsequent decreased efficacy of exenatide Niacin[7] Niacin can interfere with glucose metabolism and result in hyperglycemia Thiazide Diuretics/Triamterene[8] Can cause an increase in blood glucose levels Warfarin[3] Exenatide can delay the Tmax of warfarin and possibly increase the INR
1 None Known Thyroid Hormones[3] May cause an increase in blood glucose and decrease the effects of exenatide Oral Contraceptives[3] Can impair glucose tolerance and decrease the effects of exenatide; The rate and extent of oral contraceptive absorption can be altered. Bumetanide/Torsemide/Furosemide[3] Can cause hyperglycemia and glycosuria and decrease the efficacy of exenatide Phenytoin[3] Can exacerbate hyperglycemia and decrease the efficacy of exenatide Acetaminophen[3] The AUC and Cmax of acetaminophen can be decreased, along with an increase in the Tmax when given with or after exenatide injection Lovastatin[3] Lovastatin AUC and Cmax can be decreased, along with a delayed Tmax when given concomitantly with exenatide Digoxin[3]The Cmax of digoxin can be decreased and the Tmax of digoxin can be delyaed. Oral anti-infective agents[9] Co-administration of exenatide with an anti-infective agent can reduce the rate and extent of absorption of the oral anti-infective agents


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Drug-Food-Herb Interactions

Atorvastatin Drug/Food/Herb Interaction Chart
Severity Level Click here to see Severity Level Legend Increased Effect/Toxicity Decreased Effect
4 None Known None Known
3 None Known. None Known
2 Ethanol[10] Ethanol may increase the risk of hypoglycemia. None Known
1 None Known None Known

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Adverse Reactions/Side Effects

Exenatide was well-tolerated in phase III clinical trials, with the most common complaint of mild-to-moderate nausea.[11][12][13][14] This incidence also decreased with continued treatment. Only 2-4% of patients in phase II clinical trials withdrew from the studies to this adverse event.[14] The second most common complaint was hypoglycemia, and its incidence varied with co-administration of exenatide with other Antihyperglycemic Agents.[11][12][13][14] Other complaints included vomiting, diarrhea, headache and dizziness.[15]Combination of exenatide with a sulfonylurea resulted in the highest incidence of hypoglycemia, when compared to the combination of exenatide and metformin. [11][12][13][14]

Exenatide Adverse Reactions Chart .[16]
Incidence Body System Adverse Reactions
> 10 % Endocrine and Metabolic Hypoglycemia (in conjunction with sulfonylurea therapy 14-36%- similar frequency to placebo with metformin therapy)
Gastrointestinal Nausea (44%), Vomiting (13%), Diarrhea (13%)
Misc. Anti-exenatide Antibodies (High titers 6%, Low titers 38%)
1-10% CNS Dizziness (9%), Headache (9%)
Endocrine and Metabolic Decreased Appetite (<5%)
Gastrointestinal Dyspepsia (6%), GERD (<5%)
Neuromuscular and Skeletal Weakness (<5%)
Misc Jittery feeling (9%), Increased diaphoresis (<5%)
Post marketing/Case Reports All Abdominal distention, abdominal pain, anaphylactic reaction, angioedema, chest pain, constipation, dysgeusia, eructation, flatulence, injection site reaction, macular/papular rash, pancreatitis, pruritus, renal failure, increased serum creatinine, somnolence, urticaria, hypersensitivity pneumonitis


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Overdose Measures

In three cases of exenatide overdoses (100 mcg subcutaneously), severe nausea, severe vomiting and rapidly declining blood glucose concentrations were observed.[3] One of the three patients required parenteral glucose administration for hypoglycemia.[3] All of the patients recovered without complications.[3] The manufacturer recommends supportive care based on the patient’s signs/symptoms for an exenatide overdose.[3]

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Product Information and Distribution

Exenatide Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage
Byetta[3] Amylin Pharmaceuticals, Inc. Pen for Injection 250mcg/ml One box containing one 1.2 ML prefilled pen 66780-0210-07 2-8°C (36-46°F) when unopened; Room temperature or in the refrigerator once opened as long as the temperature is less than 25°C (77°F)
One box containing one 2.4 ML prefilled pen 66780-0210-08

Each pen will deliver 60 subcutaneous doses


  • Manufacturers/Distributors

Amylin Pharmaceuticals Inc.

Eli Lilly Homepage

  • Inactive ingredients

glacial acetic acid, mannitol , sodium acetate


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Pharmacogenomic information

No pharmacogenomic information available at the pharmacogenetics and pharmacogenomics knowledge base website

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Patient Information

  • Always administer within one hour BEFORE morning and evening meals. NEVER administer after meals.
  • Exenatide is meant for subcutaneous injection into the upper arm, upper thigh or abdomen
  • Exenatide is NOT a substitute for insulin
  • Exenatide is good for 30 days after being opened. After 30 days, throw away any unused medication.
  • Do not store the pen with the needle attached.
  • Dispose of the needle in a proper sharps container
  • Combination of exenatide with other Antihyperglycemic Agents (especially a sulfonylurea) may cause hypoglycemia.
  • Since exenatide slows gastric emptying, talk with your physician about other medications you are taking, as the effects of these drugs may be altered by delayed gastric emptying
  • Rotate injection sites.
  • Most common side effects (report to your physician if these side effects become bothersome): heartburn, injection site reactions, headache, dizziness, nausea, weight loss and decreased appetite. * Nausea tends to subside with continued use.
  • Rare Side Effects (report these side effects to your physician right away): rash, trouble breathing, signs/symptoms of hypoglycemia
  • Monitor blood glucose on a regular basis.
  • Avoid alcohol.
  • Follow a diabetic-diet
  • Discuss with physician is you are pregnant, plan to become pregnant or are breast-feeding.
  • Diet and exercise are non-pharmacological ways to control blood sugar
  • Ask your prescriber or pharmacist before you start any new prescription, herbal or over-the counter medication, or before you take any medications for cough, cold or allergies.

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References

  1. ↑ 1.0 1.1 1.2 1.3 Hinnen, Nielsen, Waninger, et al. "Incretin Mimetics and DPP-IV Inhibitors: New Paradigms for the Treatment of Type 2 Diabetes." JABFM 2006;19:612-20
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 Exenatide(Byetta®)Monograph.Clinical Pharmacology (database on the internet) Available at www.clinicalpharmacolgy.com
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24 3.25 3.26 3.27 3.28 3.29 3.30 3.31 3.32 3.33 3.34 3.35 3.36 3.37 3.38 3.39 3.40 3.41 3.42 3.43 3.44 3.45 3.46 3.47 3.48 3.49 3.50 3.51 3.52 3.53 3.54 3.55 3.56 3.57 3.58 3.59 3.60 3.61 3.62 3.63 3.64 3.65 3.66 Byetta™(exenatide) package insert. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2007 Feb.
  4. ↑ Pandit MK, Burke J, Gustafson AB, et al. Drug-induced disorders of glucose tolerance. Ann Intern Med 1993;118:529—39. ↑ Jaakkola T, Laitila J, Neuvonen PJ, et al. Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol 2006;99:44—51.
  5. ↑ IPLEX™ (mecasermin rinfabate) package insert. Glen Allen, VA: Insmed Incorporated; 2005 Dec.
  6. ↑ Gilbert RE, Cooper ME, Krum H. Drug Administration in Patients with Diabetes Mellitus, Safety Considerations. Drug Safety 1998;18:441—55.
  7. ↑ Niaspan® (niacin extended-release tablets) Miami, FL: Kos Pharmaceuticals, Inc; 2003 July.
  8. ↑ Dyrenium(R) (triamterene) package insert. Neptune, NJ: Wellspring Pharmaceuticals; 2001 Jun.
  9. ↑ Keating GM. Exenatide. Drugs. 2005; 65(12):1681-92; discussion 1693-5.
  10. ↑ Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care 2003;26:1902—12.
  11. ↑ 11.0 11.1 11.2 Buse J, Henry R, Han J, et al. "Effects of exenatide (exendin- 4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes." Diabetes Care 2004;27:2628-35.
  12. ↑ 12.0 12.1 12.2 DeFronzo R, Ratner R, Han J, Kim D, Fineman M, Baron A. "Effects of exenatide (exendin- 4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes." Diabetes Care 2005;28:1092-100.
  13. ↑ 13.0 13.1 13.2 Kendall D, Riddle M, Rosenstock J, et al. "Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea." Diabetes Care 2005;28:1083-91.
  14. ↑ 14.0 14.1 14.2 14.3 Heine RJ, Van Gaal LF, Johns D, et al. "Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial." Ann Intern Med 2005;143:559-69.
  15. ↑ Cada, Levien, Baker, et al. "Exenatide Injection" Hospital Pharmacy 2005;40(11):994-1003.
  16. ↑ Lexi-Comp (2003). Drug Information Handbook. 11th Edition., APhA.
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PUBMED References

  1. Iltz JL, Baker DE, Setter SM, et al. (2006). "Exenatide: an incretin mimetic for the treatment of type 2 diabetes mellitus." Clin Ther 28(5):652-65
  2. Zinman B, Hoogwerf BJ, Duran Garcia S (2007)"The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial." Ann Intern Med.146(7):477-85
  3. Kendall DM, Riddle MC, Rosenstock J, et al (2005) "Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea." Diabetes Care 28(5):1083-91
  4. Buse JB, Henry RR, Han J, Kim DD, et al. (2004). "Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes." Diabetes Care 27(11):2628-35.
  5. Buse JB, Klonoff DC, Nielsen LL, et al. (2007). "Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: An interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials." Clin Ther 29(1):139-53
  6. Blonde L, Klein EJ, Han J, et al. (2006) "Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes." Diabetes Obes Metab. 8(4):436-47
  7. Reuter H, Erdmann E. (2007). "Exenatide--an incretin-mimetic agent for the treatment of type 2 diabetes mellitus" Dtsch Med Wochenschr. 132(11):571-4.


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Therapeutic Class Comparison Trial Articles

  1. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, et al. (2005). "Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial." Ann Intern Med.18;143(8):559-69


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Pharmacokinetics Articles

  1. Bray. (2006). "Exenatide" Am J Health Syst Pharm. 63: 411-418
  2. Orville G. Kolterman, Dennis D. Kim, Larry Shen, et al. (2005). "Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus" Am J Health Syst Pharm.62: 173-181


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Drug Interaction Articles

  1. Prajakti A. Kothare, Danny K. W. Soon, Helle Linnebjerg, et al. (2005). "Effect of Exenatide on the Steady-State Pharmacokinetics of Digoxin" J. Clin. Pharmacol. 2005; 45; 1032 [Full Text]
  2. Kothare PA, Linnebjerg H, Skrivanek Z, et al. (2007). "Exenatide effects on statin pharmacokinetics and lipid response." Int J Clin Pharmacol Ther. 45(2):114-20
  3. Soon D, Kothare PA, Linnebjerg H, et al. (2006). "Effect of exenatide on the pharmacokinetics and pharmacodynamics of warfarin in healthy Asian men." J Clin Pharmacol. 46(10):1179-87
  4. Blase E, Taylor K, Gao HY (2005). "Pharmacokinetics of an oral drug (acetaminophen) administered at various times in relation to subcutaneous injection of exenatide (exendin-4) in healthy subjects." J Clin Pharmacol. 45(5):570-7


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Images

  1. Byetta Image
  1. Byetta Image

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External Links

  • Manufacturers/Distributors

Amylin Homepage

Eli Lilly Homepage

  • Clinical Treatment Guidelines
  1. Diabetes Mellitus: Institute for Clinical Systems Improvement (ICSI)Guidelines.
  • Diabetic Associations
  1. American Diabetes Association.
  2. American Dietetic Association.
  3. National Diabetes Education Program.
  • Patient Information Pages
  1. Byetta Homepage
  2. Byetta Let's Talk Page
  3. Managing your Diabetes;
  4. Accu-chek Glucose Meter;
  5. BD Diabetes Glucose Record Sheets
  6. Glucose Control-Diabetic Diet


  • Healthcare Professional Information Pages
  1. Byetta Package Insert
  • Other Resources
  1. American Heart Association
  2. National Cholesterol Education Program.



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