Physiologically Based Pharmacokinetic Model of Itraconazole and Two of Its Metabolites to Improve the Predictions and the Mechanistic Understanding of CYP3A4 Drug-Drug Interactions

Abstract

Physiologically based pharmacokinetic (PBPK) modeling for itraconazole using a bottom-up approach is challenging, not only due to complex saturable pharmacokinetics (PK) and the presence of three metabolites exhibiting CYP3A4 inhibition, but also because of discrepancies in reported in vitro data. The overall objective of this study is to provide a comprehensive mechanistic PBPK model for itraconazole in order to increase the confidence in its drug-drug interaction (DDI) predictions. To achieve this, key in vitro and in vivo data for itraconazole and its major metabolites were generated. These data were crucial to developing a novel bottom-up PBPK model in Simcyp (Simcyp Ltd., Certara, Sheffield, United Kingdom) for itraconazole and two of its major metabolites: hydroxy-itraconazole (OH-ITZ) and keto-itraconazole (keto-ITZ). Performance of the model was validated using prespecified acceptance criteria against different dosing regimens, formulations for 29 PK, and DDI studies with midazolam and other CYP3A4 substrates. The main outcome is an accurate PBPK model that simultaneously predicts the PK profiles of itraconazole, OH-ITZ, and keto-ITZ. In addition, itraconazole DDIs with midazolam and other CYP3A4 substrates were successfully predicted within a 2-fold error. Prediction precision and bias of DDI expressed as geometric mean fold error were for the area under the concentration-time curve and peak concentration, 1.06 and 0.96, respectively. To conclude, in this paper a comprehensive data set for itraconazole and its metabolites is provided that enables bottom-up mechanism-based PBPK modeling. The presented model is applicable for studying the contribution from the metabolites and allows improved assessments of itraconazole DDI.

Impact of Intracellular Concentrations on Metabolic Drug-Drug Interaction Studies

“…3a). However, others avoid them because the uptake mechanism of these azole compounds are not mediated via classic hepatic uptake transporters such as the OATP or OCT transporter family (29,40). Kp uu is a measure of all combined effects in a cell and provides a mechanistic tool for estimation of uptake scalars without the need for elucidating the underlying factors contributing to the net drug disposition in the cell.…”

“…3). In the case of itraconazole, the three major metabolites are equally or more potent inhibitors of CYP3A4 than the parent compound, which is a complicating factor in PBPK modeling (28,40,41). The measurement of Kp uu of the parent compound alone was however sufficient for recovering the hepatic uptake scalars.…”

A generic framework for the physiologically‐based pharmacokinetic platform qualification of PK‐Sim and its application to predicting cytochrome P450 3A4–mediated drug–drug interactions

“…Although the itraconazole PBPK model includes three inhibitory sequential metabolites resulting in a prolonged inhibitory effect, still the observed prolonged inhibition cannot be fully explained. In other PBPK studies using different PBPK platforms, for example, Prieto García et al 40 and Chen et al, 41 a general trend of the applied itraconazole PBPK models to underpredict this DDI became obvious as well. There might be a general knowledge gap in understanding this prolonged inhibitory effect of itraconazole mechanistically.…”

Recommendations for the Design of Clinical Drug–Drug Interaction Studies With Itraconazole Using a Mechanistic Physiologically‐Based Pharmacokinetic Model

“…Although ITZ PBPK models have been previously developed, these were built using a “top‐down” approach because of the uncertainty in the in vitro data required for model construction. More recently published mechanistic models demonstrated acceptable DDI simulation results, but the general applicability is uncertain because of the key in vitro data used, e.g., much larger f u,p than the experimentally determined values. In addition, the recommendations for the optimal clinical ITZ DDI study design using a PBPK model with a better mechanistic understanding are expected by pharmaceutical companies and regulatory agencies.…”