Pharmacokinetic/Pharmacodynamic Modelling of Receptor Internalization with CRTH2 Antagonists to Optimize Dose Selection

Background and Objective The chemoattractant receptor-homologous molecule expressed on T helper-2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D-2 (PGD(2)), a key mediator in inflammatory disorders. Two selective and potent CRTH2 antagonists currently in clinical development, ACT-453859 and setipiprant, were compared with respect to their (predicted) clinical efficacy. Methods Population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to characterize how plasma concentrations (PK) of ACT-453859, its active metabolite ACT-463036 and setipiprant related to their effect on blocking PGD(2)-induced internalization of CRTH2 on eosinophils (PD). Simulations were used to identify doses and dosing regimens leading to 90 % of maximum blockade of CRTH2 internalization at trough. Results A combined concentration of ACT-453859 and its metabolite ACT-463036, with weights proportional to potency (based on an eosinophil shape change assay), enabled good characterization of the PD effect. The modelling and simulation results facilitated decision making by suggesting an ACT-453859 dose of 400 mg once daily (or 100 mg twice daily) for clinically relevant CRTH2 antagonism. Conclusion Pharmacometric quantification demonstrated that CRTH2 internalization is a useful new biomarker to study CRTH2 antagonism. Ninety percent of maximum blockade of CRTH2 internalization at trough is suggested as a quantitative PD target in clinical studies.