title: Dosing rationale for liraglutide in type 2 diabetes mellitus: a pharmacometric assessment.
abstract: The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide was approved in 2010 by the US Food and Drug Administration (FDA) as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. This article provides insights into the use of pharmacometric analyses for regulatory review with a focus on the dosing recommendations. The assessment was based on the totality of exploratory and confirmatory analysis of dose-finding and pivotal clinical data and was structured around a set of key questions in accordance with current FDA review practice. For the pharmacometric review of liraglutide, the key questions focused on exposure-response relationships for effects on fasting plasma glucose, hemoglobin A(1c), and calcitonin and on variability in exposure across demographic subgroups of patients. The importance of conducting exploratory exposure-response analysis and population pharmacokinetic studies in clinical drug development to support dosing recommendations is highlighted.
authors.affiliation: Quantitative Clinical Pharmacology, Novo Nordisk A/S, Vandtårnsvej 108-110, 2860 Søborg, Denmark. si@novonordisk.com
authors.forename: Steen H
authors.initials: SH
authors.lastname: Ingwersen
authors.forename: Manoj
authors.initials: M
authors.lastname: Khurana
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Madabushi
authors.forename: Estelle
authors.initials: E
authors.lastname: Watson
authors.forename: Daniël M
authors.initials: DM
authors.lastname: Jonker
authors.forename: Tu Duyen
authors.initials: TD
authors.lastname: Le Thi
authors.forename: Lisbeth V
authors.initials: LV
authors.lastname: Jacobsen
authors.forename: Christoffer W
authors.initials: CW
authors.lastname: Tornøe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000032:analysis; D002116:Calcitonin / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005215:Fasting / Q000097:blood; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000069450:Liraglutide; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002116:Calcitonin; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069450:Liraglutide; C517652:hemoglobin A1c protein, human