Pharmacology Update

Exenatide Extended- Release for Injection (Bydureon™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a once-weekly treatment for type 2 diabetes. The new product is a subcutaneously administered extended-release form of the glucagon-like peptide-1 receptor agonist, exenatide. Exenatide extended-release is marketed by Amylin Pharmaceuticals and Alkermes PLC as Bydureon.

Indications

Exenatide-extended-release injection (ExQW) is indicated as an adjunct to diet and exercise to improve glycemic control in adult type 2 diabetics.1

Dosage

The recommended dose is 2 mg given by subcutaneous injection once weekly.1 It may be administered without regard to meals.

Exenatide-extended-release for injection is supplied as a 2 mg single-dose vial for suspension.

Potential Advantages

Compared to twice daily administration of exenatide, the once-weekly formulation provides improved glycemic control and less nausea.1,2 Patents who switched from twice-daily exenatide (ExBID) to ExQW showed additional reduction in HbA1c.3

Potential Disadvantages

Common adverse events include nausea (27%), diarrhea (16%), vomiting (11%), injection site pruritus (18%), and constipation (10%).1 Similar to immediate-release exenatide, the extended-release formulation carries the box warning for risk of thyroid C-cell tumors, including medullary thyroid carcinoma.1 It is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or patients with multiple endocrine neoplasia syndrome type 2. Exenatide has been associated with pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis. Six percent (6%) of patients develop anti-exenatide antibodies. Serious hypersensitivity has been reported during post marketing surveillance.

Comments

The once-weekly formulation is made by encapsulating exenatide in microspheres of poly-(D,L-lactide-co-glycolide).4 When injected subcutaneously, the suspension of these microspheres forms an amalgam that releases the drug over about 10 weeks with a peak around 2 weeks (therapeutic level) and another at week 6-7 (steady state).1 The approval of exenatide extended-release injection was based on a comparative study with twice-daily exenatide (DURATION-5).1,2 This 24-week study randomized 252 participants (with mean baseline HbA1c 8.5% and 8.4% for the two groups) to ExQW 2 mg every week for 24 weeks or exenatide 5 µg twice daily for 4 weeks and 10 µg twice daily for 20 weeks. The primary outcome was change in HbA1c from baseline at week 24. At week 24, ExQW resulted in a greater reduction in HGbA1c (-1.6 vs -0.9 %, P < 0.0001). There was also a greater reduction is fasting plasma glucose (-25 mg/dL vs -5 mg/dL, P < 0.001). Similar weight loss was observed between the two groups and mild-to-moderate nausea was less frequent with ExQW 14% vs 35%. Injection site pruritus was higher with ExQW compared to exenatide twice daily (18% vs 1%). Glycemic control was maintained over 1 year along with positive effects on blood pressure and lipid profile.3 In a 26-week study, ExQW was also compared to metformin, pioglitazone, and sitagliptin as monotherapy in drug-naïve type 2 patients.5 Participants (n = 820) were randomized to ExQW 2 mg weekly, metformin 2 g/d, pioglitazone 45 mg/d, or sitagliptin 100 mg/d. At 26 weeks, ExQW was similar to metformin and pioglitazone but better than sitagliptin. Patients on the maximum daily dose of sitagliptin or pioglitazone showed improved or maintained glycemic control when switched to ExQW.6 Similarly, the addition of ExQW to metformin was more effective than the addition of sitagliptin or pioglitazone.7

Clinical Implications

ExQW provides a more convenient and effective form of exenatide for the treatment of type 2 diabetes. It also may be a useful add-on therapy for patients not adequately controlled on monotherapy. There are no clinical data indicating that exenatide reduces macrovascular risk.

References

1. Bydureon Prescribing Information. San Diego, CA: Amylin Pharmaceuticals, Inc; January 2012.

2. Blevins T, et al. J Clin Endocrinol Metab 2011;96: 301-310.

3. Buse JB, et al. Diabetes Care 2010;33:1255-1261.

4. DeYoung MB, et al. Diabetes Technol Ther 2011;13: 1145-1154.

5. Russell-Jones MK, et al. Diabetes Care 2012;35:252-258.

6. Wysham C, et al. Diabet Med 2011;28:705-714.

7. Bergenstal RM, et al. Lancet 2010;376:431-439.