e effects were sustained after 6 weeks of dosing with the 1.5 mg dose.
First- and Second-Phase Insulin Secretion
Both first-and second-phase insulin secretion were increased in patients with type 2 diabetes treated with TRULICITY compared with placebo.
Insulin and Glucagon Secretion
TRULICITY stimulates glucose-dependent insulin secretion and reduces glucagon secretion. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly increased fasting insulin from baseline at Week 26 by 35.38 and 17.50 pmol/L, respectively, and C-peptide concentration by 0.09 and 0.07 nmol/L, respectively, in a Phase 3 monotherapy study. In the same study, fasting glucagon concentration was reduced by 1.71 and 2.05 pmol/L from baseline with TRULICITY 0.75 mg and 1.5 mg, respectively.
Gastric Motility
Dulaglutide causes a delay of gastric emptying. The delay is largest after the first dose and diminishes with subsequent doses.
Cardiac Electrophysiology (QTc)
The effect of dulaglutide on cardiac repolarization was tested in a thorough QTc study. Dulaglutide did not produce QTc prolongation at supratherapeutic doses of 4 and 7 mg.
12.3 Pharmacokinetics
The pharmacokinetics of dulaglutide is similar between healthy subjects and patients with type 2 diabetes mellitus. Following subcutaneous administration, the time to maximum plasma concentration of dulaglutide at steady-state ranges from 24 to 72 hours, with a median of 48 hours. After multiple-dose administration of 1.5 mg to steady state, the mean peak plasma concentration (Cmax) and total systemic exposure (AUC) of dulaglutide were 114 ng/mL (range 56 to 231 ng/mL) and 14,000 ng h/mL (range 6940 to 26,000 ng/mL), respectively; accumulation ratio was approximately 1.56. Steady-state plasma dulaglutide concentrations were achieved between 2 and 4 weeks following once weekly administration. Site of subcutaneous administration (abdomen, upper arm, and thigh) had no statistically significant effect on the exposure to dulaglutide.
Absorption – The mean absolute bioavailability of dulaglutide following subcutaneous administration of single 0.75 mg and 1.5 mg doses was 65% and 47%, respectively.
Distribution – The mean volumes of distribution after subcutaneous administration of TRULICITY 0.75 mg and 1.5 mg to steady state were approximately 19.2 L (range 14.3 to 26.4) and 17.4 L (range 9.3 to 33), respectively.
Metabolism – Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways.
Elimination – The mean apparent clearance at steady state of dulaglutide is approximately 0.111 L/hr for the 0.75 mg dose, and 0.107 L/hr for the 1.5 mg dose. The elimination half-life of dulaglutide for both doses is approximately 5 days.
Specific Populations
No dose adjustment of dulaglutide is needed based on age, gender, race, ethnicity, body weight, or renal or hepatic impairment. The effects of intrinsic factors on the PK of dulaglutide are shown in Figure 1.
Figure 1: Impact of intrinsic factors on dulaglutide pharmacokinetics.
Renal – Dulaglutide systemic exposure was increased by 20, 28, 14 and 12% for mild, moderate, severe, and ESRD renal impairment sub-groups, respectively, compared to subjects with normal renal function. The corresponding values for increase in Cmax were 13, 23, 20 and 11%, respectively (Figure 1). [see Dosage and Administration (2.3), Warning and Precautions (5.5), Use in Specific Population (8.7)].
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