Clinical Pharmacology Strategy for Registration in Japan with a Case Example of Posaconazole, a Globally Approved Triazole Antifungal Drug with Broad-spectrum Antifungal Activity

Typically, to support regulatory drug approval in Japan, an appropriate justification of the dosage regimen (s)in the target indication proposed in Japanese patient population based on the overall clinical data and evidence is required. More specifically, when using foreign data and/or discussing extrapolation of data/interpretation into Japanese targeted population, it is important to understand the similarity and consistency of clinical data between Japanese and non-Japanese populations("ethnicity")in healthy participants and targeted patients, as well as between healthy participants and patients("disease status")in Japanese and non-Japanese populations. This is usually supported by pharmacokinetic, pharmacodynamic(marker of efficacy), and safety data obtained from clinical studies. In this review, the concept above is thoroughly introduced with the case example of posaconazole, a globally approved triazole antifungal drug with broad-spectrum antifungal activity including in Japan, applying a model-informed approach for the dose justification of posaconazole in Japanese population as either high-risk patients with fungal infections (prophylaxis)or patients with fungal infections(treatment)using pharmacokinetic data together with exposure-response relationships. In the case of applying for regulatory approval for posaconazole, there were difficulties in interpretating the effect of ethnicity and disease status due to potential confounding and mitigating lack of clinical data for a part of targeted patient populations. Taking that into consideration, the dosage and dosing regimen for Japanese patients with target indication were justified based on the totality of comprehensive relationships among the populations with respect to ethnicity and disease status, as well as results from model-informed approaches.