Evaluation of the Drug–Drug Interaction Potential of Treosulfan using a Physiologically-Based Pharmacokinetic Modelling Approach

AIMS The aim of this work is the development of a mechanistic Physiologically Based Pharmacokinetic (PBPK) model using in vitro to in vivo extrapolation (IVIVE) to conduct a DDI (drug-drug interaction) assessment of treosulfan against two cytochrome p450 isoenzymes and P-gp substrates. METHODS A PBPK model for treosulfan was developed de-novo based on literature and unpublished clinical data. The PBPK DDI analysis was conducted using the FDA DDI index drugs (probe substrates) midazolam, omeprazole, and digoxin for CYP3A4, CYP2C19, and P-gp, respectively. Qualified and documented PBPK models of the probe substrates have been adopted from an open-source online model database. RESULTS The PBPK model for treosulfan, based on both in vitro and in vivo data, was able to predict the plasma concentration-time profiles and exposure levels of treosulfan applied for a standard conditioning treatment. A medium and low potential for DDI on CYP3A4 (AUCr max = 2.23) and CYP2C19 (AUCr max = 1.6) was predicted, respectively, using probe substrates midazolam and omeprazole. Treosulfan was not predicted to cause a DDI on P-gp. CONCLUSION Medicinal products with a narrow therapeutic index (e. g. digoxin) that are substrates for CYP3A4, CYP2C19, or P-gp should not be given during treatment with treosulfan. However, considering the comprehensive treosulfan-based conditioning treatment schedule and the respective PK properties of the concomitantly used drugs (e.g., half-life), the potential for interaction on all evaluated mechanisms would be low (AUCr < 1.25), if concomitantly administered drugs are dosed either 2 h before or 8 h after the 2 h i.v. infusion of treosulfan.