Comparable liraglutide pharmacokinetics in pediatric and adult populations with type 2 diabetes: a population pharmacokinetic analysis

Abstract

Background and objective: The safety, tolerability, and pharmacokinetics of the once-daily human glucagon-like peptide-1 (GLP-1) analog liraglutide have been evaluated in pediatric patients aged greater than 10 years with type 2 diabetes (T2D). In this study, a population pharmacokinetic analysis was compared to the pediatric pharmacokinetic data with those from two clinical pharmacology trials in adults with T2D.

Methods: A one-compartment pharmacokinetic model previously found to adequately describe the pharmacokinetics of liraglutide in adults with T2D was applied to the evaluation of 13 pediatric subjects (10-17 years of age) with T2D. Steady-state estimates for apparent clearance (CL/F) for individual subjects and corresponding dose were used to derive the area under the plasma-concentration time curve from 0-24 h (AUC24) and investigate dose proportionality in the pediatric trial. A covariate analysis evaluated the effects of body weight, gender, and age category (pediatric/adult) on liraglutide exposure.

Results: Dose proportionality in the dose range of 0.3-1.8 mg was indicated by the model-derived AUC24 slope: 1.05 (95% CI 0.96-1.15). Consistent with findings from adult trials, body weight and gender were relevant covariates for liraglutide exposure in the pediatric population. The CL/F estimates, and thus exposure, for the pediatric subjects with T2D were similar to those in the adult trials.

Conclusion: Based on this population pharmacokinetic analysis, the liraglutide dose regimen that was found to be clinically effective in adults is predicted to achieve the same range of exposure in the pediatric population (10-17 years of age) with a pre-trial body weight range of 57-214 kg.

Trial registration: ClinicalTrials.gov NCT00943501 NCT00993304.

Figures

Fig. 1

Observed and model-derived liraglutide concentration profiles in the pediatric population by dose level. Figures with bars geometric mean (95% confidence interval) of the observed liraglutide concentration. Lines geometric means of the individual (post hoc) model-derived concentration–time profiles

Fig. 2

Dose proportionality test based on model-estimated AUC24, which, in turn, was derived from estimated CL/F. Solid line represents geometric mean AUC24, as estimated by the linear mixed-effects model of log (AUC24) versus log (dose). Model-derived AUC24 slope: 1.05 [0.96–1.15]95 % CI. AUC area under the plasma–concentration time curve, AUC24 AUC from zero to 24 h, CL/F apparent clearance, CI confidence interval

Fig. 3

Geometric mean ratios and 90 % CI of effect of demographic covariates (gender, body weight, and age group) on AUC24 relative to a reference subject (90 kg adult female). The solid line represents the ratio of 1 (i.e. no pharmacokinetic relevance). Broken lines delineate the acceptance interval for bioequivalence (0.8–1.25); these limits were used to determine drug exposure equivalence in this analysis. AUC area under the plasma–concentration time curve, AUC24 AUC from zero to 24 h, CI confidence interval

Fig. 4

a AUC24 versus body weight for liraglutide 1.8 mg once daily, according to age category (pediatric subjects from Trial 1 vs. adult subjects from Trials 2 and 3). The completely superimposed lines show the model-predicted AUC24 versus body weight for pediatric and adult subjects, respectively. The estimated AUC24 has been normalized to a 1.8 mg dose for four pediatric subjects, reaching a maximum dose of 0.3 (n = 1) or 0.6 mg (n = 3). b Model-derived typical steady-state concentration–time profiles for pediatric and adult subjects receiving 1.8 mg liraglutide. The figure shows results for pediatric and adult populations with body weight and gender adjusted (both populations with body weight of 90 kg and 50 % female gender composition) in order to minimize confounding. AUC area under the plasma–concentration time curve, AUC24 AUC from zero to 24 h