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.

Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed‐ratio combination therapy

“…6,25,28 Furthermore, covariate analysis demonstrated that there was no difference in IDeg dose-normalized exposure (AUC) with IDegLira compared with IDeg alone, supporting the findings of the single-dose PK study. A lower mean steady-state liraglutide exposure was observed consistently across the 2 studies (including in healthy subjects and those with T2D), when dosed as part of IDegLira compared with liraglutide alone and was within the criterion set for bioequivalence.…”

“…Taken together, these findings are consistent with previous results obtained for covariate effects for IDeg (data on file) and liraglutide. 25 The modeled concentration-time profile of IDeg at steady state following IDegLira administration was similar to the profile for IDeg dosed alone ( Figure 1C). The PK profile demonstrated that exposure is distributed evenly across the 24-hour dosing interval.…”

“…These results were largely consistent with the results seen in the individual IDeg and liraglutide clinical development programs. 25,[29][30][31] Dose/exposure-response analyses showed that across the entire range of doses and exposures, the effect of IDegLira on HbA 1c levels was larger than the effect of both IDeg and liraglutide administered alone. It can therefore be concluded that the IDeg and liraglutide components contribute distinctly to the glycemic effect of IDegLira throughout the studied dose and exposure ranges.…”

“…For liraglutide, sex was also included in the model, as sex has previously been shown to have an effect on CL/F for liraglutide. 25 Further methodological details are available in the Appendix.…”

Liraglutide's Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Pediatric Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

“…20,22,23 Although female sex was associated with a lower weight-adjusted drug clearance, this did not impact clinical response to the 1.2 and 1.8 mg liraglutide doses. 24 Body weight significantly affected the PK of liraglutide. Although increasing body weight resulted in lower drug exposure (area under the concentration-time curve [AUC]), the clinical response was unaffected.…”