Pharmacokinetics and efficacy of a biweekly dosage formulation of exenatide in Zucker diabetic fatty (ZDF) rats.
OBJECTIVE
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).


CONCLUSIONS
DA-3091 has the potential to be used safely and efficaciously in a biweekly dosing regimen.
Kwak
Hyun-Hee
HH
Biopharmaceutical Research Laboratory, Dong-A Pharm. Co. Ltd., Gyeonggi, 446-905, Republic of Korea.
Shim
Won-Sik
WS
Hwang
Seongmee
S
Son
Mi-Kyung
MK
Kim
Yoon-Ji
YJ
Kim
Tae-Hyoung
TH
Yoon
Zee-Hye
ZH
Youn
Hyun-Jun
HJ
Lee
Ghun-Il
GI
Kang
Soo-Hyoung
SH
Shim
Chang-Koo
CK
D000818:Animals; D002626:Chemistry, Pharmaceutical; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004334:Drug Administration Schedule; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008863:Microspheres; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D014688:Venoms / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide