Therapeutic Protein Drug–Drug Interactions

Abstract

Most of the reported drug–drug interactions (DDIs) involving therapeutic proteins (TPs) have been mild in nature and did not require dose adjustments. The majority of observed TP‐DDI occurred when small‐molecule drugs were coadministered with cytokine‐modulating TP. However, alterations in P‐glycoprotein and plasma proteins such as albumin or α acid glycoprotein have also been implicated in potential DDI. A new class of TP, antibody–drug conjugates, can potentially be involved as victims of DDI when clearance of the released drug is impaired. Both the 2007 EMA “Guideline on the Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins” and 2012 FDA draft “Guidance on Drug Interaction Studies” contain recommendations for the TP‐DDI evaluation. Comprehensive assessment of the DDI risk for TPs requires a systematic, science‐driven approach that takes into account clearance mechanisms of the TP, its pharmacology, the target patient population, and expected concomitant medications. To date, conducting a clinical DDI study is the most reliable approach for TP‐DDI assessment. The approaches include population PK modeling, coadministration with cytochrome P450 (CYP) substrate cocktail, assessment of CYP expression in tissue biopsies, and measurements of the systemic cytokine concentrations.