Pharmacokinetic/pharmacodynamic analyses of chymase inhibitor SUN13834 in NC/Nga mice and prediction of effective dosage for atopic dermatitis patients

Abstract

A chymase inhibitor SUN13834 has been shown to improve skin condition in animal models for atopic dermatitis. In the present study, effective dosages of SUN13834 for atopic dermatitis patients were predicted by pharmacokinetic/pharmacodynamic (PK/PD) analyses of SUN13834 in NC/Nga mice, which spontaneously develop atopic dermatitis-like skin lesions. For the PK/PD analyses, we utilized the minimum effective plasma concentration of unbound SUN13834 in late-phase reaction of trinitrochlorobenzene (TNCB)-induced biphasic dermatitis in mice, based on the assumption that the minimum effective plasma concentrations are the same among the two animal models. In late-phase reaction of biphasic dermatitis, SUN13834 was most effective when its plasma concentration was highest at the elicitation, and the minimum effective plasma concentration of unbound SUN13834 at the elicitation was calculated to be 0.13–0.2ng/mL. Oral administration of SUN13834 improved dermatitis in NC/Nga mice at 15mg/kg (twice a day; bid) and 30mg/kg (once a day; qd), but not at 60mg/kg (every other day; eod). At the three dosages, the duration times over the plasma level of 0.13–0.2ng/mL were 16.1–20.3, 10.7–12.2 and 7.8–8.8h, respectively, suggesting an importance of maintenance of the minimum effective plasma concentration for at least about 10–12h. The clinical effective dosage predicted in this paper is also discussed in relation to a recently conducted Phase 2a study.