Posaconazole is a triazole antifungal compound that, like other azole antifungal compounds, inhibits lanosterol 14 α-demethylase(cytochrome P450 family 51), an enzyme essential for the biosynthesis of ergosterol for the cell membrane of microorganisms. As a result, posaconazole produces a broad-spectrum antifungal effect. Posaconazole has been approved in multiple countries and regions including the United States and the European Union for prophylaxis and treatment of invasive fungal infections.
Typically, to support regulatory drug approval in Japan, appropriate justification of the dosage regimen(s) in the target indication proposed in the Japanese patient population based on overall clinical data and evidence is generally required. More specifically, when using foreign (non-Japanese) data and/or discussing extrapolation of data/interpretation into the Japanese population, it is important to understand the similarity and consistency of clinical data between Japanese vs non-Japanese populations (“ethnicity”) in healthy participants and target patient populaiton, as well as between healthy participants vs patients (“disease status”) in Japanese and non-Japanese populations. This is usually supported by pharmacokinetic (PK), pharmacodynamic, and safety data obtained from clinical studies. This concept is illustrated with the case example of posaconazole, applying a model-informed approach for dose justification in Japanese patients at high-risk of fungal infections (prophylaxis) or patients with fungal infections (treatment) using PK data together with exposure-response relationships.
In applying for regulatory approval for posaconazole, there were difficulties in interpretating the effect of ethnicity and disease status due to confounding factors across Japanese and global populations. A simultaneous population PK model for tablet and intravenous formulation was therefore developed on the basis of a data set including Japanese and global data. Since no Japanese prophylaxis patients were enrolled in the phase 3 study, the PK profiles in Japanese prophylaxis patients were predicted to inform the expected efficacy and safety profiles of posaconazole in the Japanese prophylaxis population, using the population PK model and demographic covariate information obtained from the published literature. The predicted PK profiles and exposure distributions in Japanese patients were compared against data from global patients, also considering exposure-response relationships related to efficacy and safety. Based upon the globally approved dosing regimen, the posaconazole exposure distribution was predicted to be the highest in Japanese patients. A review of the demographic data revealed that the Japanese treatment patients had a lower body weight and increased age compared with the foreign prophylaxis patients. Therefore, a simulation approach was applied using virtual patient populations in order to mimic the distribution of these factors in the foreign prophylaxis patients, indicating that the body weight and age differences primarily accounted for the higher exposures observed in the Japanese treatment patients and confirming that the recommended clinical dosing regimen proposed in Japanese patients was expected to provide efficacy comparable to or higher than that established in global patients. These analyses supported regulatory approval in Japan with identical dosing regimens in Japanese patients as those approved globally.