Dose extrapolation to special populations using physiologically based pharmacokinetic modelling technique

Physiologically based pharmacokinetic modeling (PBPK) is a new generation modeling method that is increasingly being applied in the context of two emerging concepts: model-informed drug development (MIDD) and model-informed precision dosing (MIPD). The mechanistic nature of PBPK modeling and its handling of extensive internal parameters is its most significant advantage over classical pharmacokinetic modeling methods, which are empirical modeling techniques. PBPK modeling is particularly capable of quantifying pharmacokinetic changes in varying physiological and anatomical environments. This capability allows for dose extrapolation from adult healthy (normal) populations to special populations. Thus, preliminary data on the altered pharmacokinetic characteristics of special populations can be generated. Due to these advantages, in our study, a pharmacokinetic profile was determined in a special population using PBPK modeling, and dose extrapolation was performed. Itraconazole, along with its three metabolites, inhibits its own metabolic enzyme. This auto-inhibition leads to drug accumulation and prolonged half-life with multiple doses. Consequently, itraconazole exhibits a complex and non-linear pharmacokinetic profile. Additionally, itraconazole's logP value exceeding 5 indicates high lipophilicity. Highly lipophilic drugs, due to their increased distribution into adipose tissue in obese populations compared to normal-weight populations, result in both a more prolonged half-life than anticipated and a lower plasma itraconazole concentration profile relative to normal-weight individuals. These pharmacokinetic characteristics delay the time to reach effective therapeutic concentrations in obese populations. In this scenario, determining an alternative dosing regimen (especially a loading dose) to achieve effective treatment in the obese population is crucial for itraconazole. In our study, alternative dosing regimens were determined for both obese and normal-weight populations to achieve effective treatment values at an early stage. When an alternative dosing regimen was applied, itraconazole reached the target trough concentration on day 5 in the obese population, whereas the target trough concentration could not be reached for 21 days with the label treatment. The itraconazole label does not include separate dosing regimens for treatment and prophylaxis. However, a meta-analysis published in 2018 recommends a target trough concentration of 0,25 mg/L for itraconazole prophylaxis and 0,5 mg/L for treatment. Especially due to auto-inhibition, there is a potential for rapid escalation to toxic concentrations as the itraconazole dose increases. Maintaining a low itraconazole trough concentration serves as a precaution against reaching toxic concentrations. In our study, alternative prophylaxis regimens were also determined. Thus, the toxicity rate could be reduced by an average of 13,4% in the obese population and by an average of 15,2% in the normal-weight population according to the simulation of the alternative treatment regimen.