Clinical Pharmacokinetics of Dulaglutide in Patients with Type 2 Diabetes: Analyses of Data from Clinical Trials.
OBJECTIVE
Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were characterized in patients with T2D and healthy subjects.


METHODS
The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D. The effects of potential covariates on dulaglutide population pharmacokinetics were evaluated using nonlinear mixed-effects models.


RESULTS
Dulaglutide gradually reached the maximum concentration in 48 h and had a terminal elimination half-life of 5 days. Steady state was achieved between the second and fourth doses. The accumulation ratio was 1.56 for the 1.5 mg dose. Intra-individual variability estimates for the area under the plasma concentration-time curve and the maximum concentration were both <17% [coefficient of variation (CV)]. There was no difference in pharmacokinetics between injection sites (arm, thigh or abdomen). Dulaglutide pharmacokinetics were well described by a two-compartment model with first-order absorption and elimination. The population clearance was estimated at 0.126 L/h [inter-individual variability (CV) 33.8%]. Age, body weight, sex, race and ethnicity did not influence dulaglutide pharmacokinetics to any clinically relevant degree.


CONCLUSIONS
The pharmacokinetics of dulaglutide support once-weekly administration in patients with T2D. The pharmacokinetic findings suggest that dose adjustment is not necessary on the basis of body weight, sex, age, race or ethnicity or site of injection.
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Jeanne S
JS
Geiser
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Michael A
MA
Heathman
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Xuewei
X
Cui
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Jennifer
J
Martin
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Corina
C
Loghin
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Jenny Y
JY
Chien
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA. de_la_pena_amparo@lilly.com.
Amparo
A
de la Peña
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004333:Drug Administration Routes; D005260:Female; D004763:Glucagon-Like Peptides / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000097:blood; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D004763:Glucagon-Like Peptides; C555680:dulaglutide