Pharmacokinetics and pharmacodynamics of inhaled GLP-1 (MKC253): proof-of-concept studies in healthy normal volunteers and in patients with type 2 diabetes.
MKC253 is glucagon-like peptide 1 (GLP-1, 7-36 amide) adsorbed onto Technosphere microparticles for oral inhalation. The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5 min, and levels returned to baseline within 30 min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose excursions in subjects with type 2 diabetes. An E(max) (maximum effect) model described the relationship between GLP-1 concentration and insulin release. The variability in the E(max) may be due to differences in baseline glucose levels, differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.
Marino
M T
MT
MannKind Corporation, Paramus, New Jersey, USA. mmarino@mannkindcorp.com
Costello
D
D
Baughman
R
R
Boss
A
A
Cassidy
J
J
Damico
C
C
van Marle
S
S
van Vliet
A
A
Richardson
P C
PC
D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D002149:Energy Intake; D005260:Female; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon