Drug Interactions for Low-Dose Inhaled Nemiralisib: A Case Study Integrating Modeling, In Vitro, and Clinical...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Clinical Pharmacology
• In Silico Modeling

Background:

• Nemiralisib is a low-dose inhaled phosphoinositide 3-kinase delta inhibitor.
• In vitro studies identified nemiralisib as a substrate and inhibitor of cytochrome P450 (P450) 3A4 and a P-glycoprotein (P-gp) substrate.
• Assessing drug-drug interaction (DDI) risks is crucial for inhaled medications.

Purpose of the Study:

• To evaluate the DDI risk of inhaled nemiralisib using an integrated in silico, in vitro, and clinical approach.
• To develop a physiologically based pharmacokinetic (PBPK) model for inhaled nemiralisib to predict DDI.
• To assess both victim and perpetrator DDI potential of nemiralisib.

Main Methods:

• A clinical DDI study coadministering nemiralisib with itraconazole (a P450 3A4/P-gp inhibitor).
• Development of an inhaled PBPK model using Simcyp software for extrapolation.
• Retrospective and prospective simulations to predict DDI risks with other P450 3A4 inhibitors and substrates.

Main Results:

• Systemic exposure (AUC0-inf) of nemiralisib increased 2.01-fold when coadministered with itraconazole.
• The PBPK model accurately predicted observed clinical DDI data (simulated AUC0-inf ratio 2.3 vs. observed 2.01).
• Simulations predicted weak, manageable DDIs with macrolides (clarithromycin, erythromycin) and negligible perpetrator effects on midazolam and theophylline.

Conclusions:

• An integrated approach combining in silico, in vitro, and clinical data successfully assessed and discharged DDI risks for nemiralisib.
• The developed inhalation PBPK model facilitates bespoke DDI risk assessment for inhaled drugs.
• This strategy ensures patient safety and supports the progression of nemiralisib in clinical trials.