Biologic-drug interactions between therapeutic protein and small-molecule drugs

Abstract

Therapeutic proteins (TPs) are becoming extremely important as therapeutic agents. Refinements in molecular structure have warranted long-term administration with sig- nificantly increase on efficacy and adhesion to therapeutic regimens by the patients, broadening the scope of indications for this class of therapy. Therefore, some biologics have become the standard of care in several therapeutic areas, such as inflammatory and oncology. A consequence of the increasing biologics indications is the concomitant administration with well-established small-molecule drugs (sMDs). Patent expiration of several biologics, such as monoclonal Antibodies (mAbs), may also contribute to the in- creasing use of TPs since biossimilars become available at more appealing prices. A bet- ter understanding of biologic-drug interactions (BDIs) is necessary to avoid the decrease of therapeutic regimens efficacy. By the existing regulatory guidance, the development of a new sMD includes an evaluation of the potential drug-drug interactions (DDIs) for concomitant medications. Only a few drug interaction studies have been performed with macromolecules since those studies, involving TPs, are inherently complicated. Few clinically relevant animal models available, long elimination half-lives, and complex elim- ination pathways, which differ from the classical cytochrome P450 (CYP450) system, are among the expected difficulties. In spite of the pharmacokinetic (PK) interactions, the most important and well-studied mechanism of interaction, pharmacodynamics (PD) in- teractions may also represent a possible explanation for several BDIs. The present re- view of the current literature encompasses several BDIs involving TPs (either as perpe- trators or as victims) and their specific mechanism of interaction.