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Pharmacokinetics and Efficacy of a Biweekly Dosage Formulation of Exenatide in Zucker Diabetic Fatty (ZDF) Rats

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Abstract

Purpose

To develop an improved sustained-release (SR) formulation of exenatide (a therapy for patients with type 2 diabetes mellitus) in a biweekly dosage form with therapeutic efficacy comparable to that achieved with twice-daily injections of the drug.

Methods

A SR formulation of exenatide, DA-3091, was prepared by single-emulsion solvent evaporation using poly(D,L-lactide-co-glycolide). Plasma exenatide, as well as plasma insulin, non-fasting blood glucose and HbA1c concentrations, and changes in food intake and body weight were evaluated in both Zucker diabetic fatty (ZDF) and ZDF lean control rats.

Results

After a single SC administration of DA-3091 (i.e., 2 mg/kg of exenatide), the plasma exenatide concentration increased and remained elevated in both groups. The concentrations of non-fasting blood glucose and HbA1c decreased significantly following a single SC injection of DA-3091 only in ZDF rats, indicating that the effects of exenatide are dependent on blood glucose concentration. On the other hand, both food intake and body weight gain were reduced in ZDF and ZDF lean control rats. A single injection of DA-3091 (i.e., 2 mg/kg of exenatide) lowered non-fasting blood glucose and HbA1c concentrations more effectively than 14 days of twice-daily administration of exenatide (i.e., 1.96 mg/kg of exenatide).

Conclusion

DA-3091 has the potential to be used safely and efficaciously in a biweekly dosing regimen.

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Abbreviations

AUC:

the area under the plasma concentration time curve

Cmax :

the maximum plasma concentration

DPP-4:

dipeptidyl peptidase-4

GLP-1:

glucagon-like peptide-1

HbA1c:

glycosylated hemoglobin

PLGA:

poly(D,L-lactide-co-glycolide)

Tmax :

the time to reach the maximum concentration

ZDF:

Zucker diabetic fatty

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ACKNOWLEDGMENTS

This work was supported by the Ministry for Health, Welfare and Family Affairs, (A080017) and by the Ministry of Science and Technology through the National Research Laboratory Program (ROA-2006-000-10290-0), Republic of Korea.

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Authors and Affiliations

  1. Biopharmaceutical Research Laboratory, Dong-A Pharm. Co. Ltd., Gyeonggi, 446-905, Republic of Korea

    Hyun-Hee Kwak, Mi-Kyung Son, Yoon-Ji Kim, Tae-Hyoung Kim, Zee-Hye Yoon, Hyun-Jun Youn, Ghun-Il Lee & Soo-Hyoung Kang

  2. National Research Laboratory for Transporters Targeted Drug Design, College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea

    Hyun-Hee Kwak, Won-Sik Shim, Seongmee Hwang & Chang-Koo Shim

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  1. Hyun-Hee Kwak
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Correspondence to Chang-Koo Shim.

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Kwak, HH., Shim, WS., Hwang, S. et al. Pharmacokinetics and Efficacy of a Biweekly Dosage Formulation of Exenatide in Zucker Diabetic Fatty (ZDF) Rats. Pharm Res 26, 2504–2512 (2009). https://doi.org/10.1007/s11095-009-9966-3

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  • DOI: https://doi.org/10.1007/s11095-009-9966-3

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