Clinical Pharmacokinetics of Dulaglutide in Patients with Type 2 Diabetes: Analyses of Data from Clinical Trials

Abstract

Background and 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.

Conclusion

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.

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Acknowledgments

This work was sponsored by Eli Lilly and Company. The authors thank the trial investigators, trial staff and trial participants for their contributions. The authors also express their gratitude to Dr. Helen Salter and Ms. Lisa Toth for providing medical writing support, and to Dr. Jessie L. Fahrbach, Dr. Sherry Martin, Dr. Malcolm Mitchell, Dr. Archana Chaudhary, Dr. Karen Schneck, Dr. Lai San Tham and Mr. Siak Leng Choi for providing scientific review and technical support.

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Correspondence to Amparo de la Peña.

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Declarations of interest

JSG, MAH, XC, JM, CL, JYC and AdlP are employees and shareholders of Eli Lilly and Company.

Scientific meeting presentation

This work was presented in part at the American Diabetes Association’s 74th Scientific Sessions in San Francisco, CA, USA, in June 2014, and at the European Association for the Study of Diabetes 50th Annual Meeting in Vienna, Austria, in September 2014.

Ethical standards

All clinical studies described herein were approved by the appropriate ethics committee and were therefore performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All subjects gave their informed consent prior to their inclusion in the studies. This manuscript does not contain animal studies or data.

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Geiser, J.S., Heathman, M.A., Cui, X. et al. Clinical Pharmacokinetics of Dulaglutide in Patients with Type 2 Diabetes: Analyses of Data from Clinical Trials. Clin Pharmacokinet 55, 625–634 (2016). https://doi.org/10.1007/s40262-015-0338-3

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Keywords

  • Population Pharmacokinetic Analysis
  • Dose Proportionality
  • Target Patient Population
  • Combine Phase
  • Pharmacokinetic Finding