Population Pharmacokinetics and Exposure-Response Modeling Analyses of Golimumab in Children and Young Adults With...

Golimumab was recently evaluated in a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (T1GER study) for safety and efficacy in children and young adults with newly diagnosed type 1 diabetes (T1D). Golimumab showed significant treatment effect where endogenous insulin production was preserved and clinical and metabolic parameters were improved. The objective of this report was to evaluate pharmacokinetic (PK) and pharmacodynamic data from the T1GER study by developing a population pharmacokinetic (PopPK) model and performing exposure-response (ER) analyses. The PopPK model was developed using data from the T1D study and 2 other pediatric studies with golimumab in ulcerative colitis and in polyarticular juvenile idiopathic arthritis. A 1-compartment model with first-order absorption and elimination was applied to describe the concentration-time profiles. Typical parameters normalized to the values in subjects with a standard weight of 70 kg were apparent clearance, 0.850 L/day; apparent volume of distribution, 16.0 L; and absorption rate constant, 1.01/day. From the ER analyses, no clear trends were observed for changes in both C-peptide area under the concentration-time curve and hemoglobin A_1c levels for the relatively narrow exposure ranges following the body surface area-based dosing regimen used in this study. In conclusion, the developed PopPK model was able to adequately describe the observed PK of golimumab in patients with T1D. Although golimumab showed significant treatment effect, the ER analyses did not show clear trends within the active treatment group, which may indicate that the exposure from this T1D-specific dosing regimen was at the plateau of the ER curve.