Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus.
OBJECTIVE
The pharmacology and tolerability of exenatide in patients with type 2 diabetes mellitus were studied.


METHODS
Two randomized, single-blind, placebo-controlled studies were conducted. Treatment with oral antidiabetic agents was stopped 14 days before study initiation. In the first study (study A), eight subjects received placebo, 0.1-, 0.2-, 0.3-, and either 0.4-microg/kg exenatide or placebo five minutes before a meal combined with liquid acetaminophen (to assess the rate of gastric emptying) on days 1, 3, 5, 7, and 9. In the second study (study B), subjects received a single s.c. dose of exenatide or placebo on consecutive days. Part 1 of study B used exenatide doses of 0.01 and 0.1 microg/ kg; 0.02-, 0.05-, and 0.1-microg/kg doses were given in part 2. After an overnight fast, the study drug was injected 15 minutes before a meal (part 1) and before a meal and acetaminophen (part 2). Parts 1 and 2 of study B enrolled six and eight patients, respectively.


RESULTS
In both studies, plasma exenatide pharmacokinetic profiles appeared dose proportional. Exenatide doses of 0.02-0.2 microg/kg dose-dependently lowered postprandial glucose excursions. Exenatide suppressed postprandial plasma glucagon and slowed gastric emptying. There were no serious adverse events and no patient withdrawals related to treatment. Nausea and vomiting were the most common adverse events and were mild to moderate in severity at doses ranging from 0.02 to 0.2 microg/kg.


CONCLUSIONS
Administration of preprandial exenatide by s.c. injection resulted in dose-proportional exenatide pharmacokinetics and antidiabetic pharmacodynamic activity. At doses ranging from 0.02 to 0.2 microg/kg, exenatide dose-dependently reduced postprandial plasma glucose excursion by insulinotropism, suppression of plasma glucagon, and slowing of gastric emptying.
Kolterman
Orville G
OG
Amylin Pharmaceuticals Inc., 9360 Towne Centre Drive, Suite 110, San Diego, CA 92121, USA. okolterman@amylin.com
Kim
Dennis D
DD
Shen
Larry
L
Ruggles
James A
JA
Nielsen
Loretta L
LL
Fineman
Mark S
MS
Baron
Alain D
AD
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001786:Blood Glucose / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000077270:Exenatide; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects / Q000502:physiology; D005934:Glucagon / Q000097:blood / Q000187:drug effects; D006801:Humans; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010455:Peptides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019518:Postprandial Period / Q000187:drug effects / Q000502:physiology; D016037:Single-Blind Method; D014688:Venoms / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014839:Vomiting / Q000139:chemically induced
D001786:Blood Glucose; D007328:Insulin; D010455:Peptides; D014688:Venoms; D005934:Glucagon; D000077270:Exenatide