Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.
In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.
Kothare
Prajakti A
PA
Global PK/PD and Trial Simulations, Eli Lilly and Company, Indianapolis, IN 46285, USA. kotharep@lilly.com
Linnebjerg
Helle
H
Isaka
Yoshitaka
Y
Uenaka
Kazunori
K
Yamamura
Ayuko
A
Yeo
Kwee Poo
KP
de la Peña
Amparo
A
Teng
Choo Hua
CH
Mace
Kenneth
K
Fineman
Mark
M
Shigeta
Hirofumi
H
Sakata
Yukikuni
Y
Irie
Shin
S
D019540:Area Under Curve; D044466:Asian People; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000208:ethnology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000097:blood; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D007564:Japan; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010455:Peptides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016037:Single-Blind Method; D013997:Time Factors; D016896:Treatment Outcome; D014688:Venoms / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014839:Vomiting / Q000139:chemically induced
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D005934:Glucagon; D000077270:Exenatide