title: How current understanding of clearance mechanisms and pharmacodynamics of therapeutic proteins can be applied for evaluation of their drug-drug interaction potential.
abstract: Increasing use of therapeutic proteins (TPs) in polypharmacy settings calls for more in-depth understanding of the biological interactions that can lead to increased toxicity or loss of pharmacological effect. Factors such as patient population, medications that are likely to be coadministered in that population, clearance mechanisms of a TP, and concomitant drugs have to be taken into account to determine the potential for drug-drug interactions (DDIs). The most well documented TP DDI mechanism involves cytokine-mediated changes in drug-metabolizing enzymes. Because of the limitations of the current preclinical models for addressing this type of DDI, clinical evaluation is currently the most reliable approach. Other DDI mechanisms need to be addressed on a case-by-case basis. These include altered clearance of TPs resulting from the changes in the target protein levels by the concomitant medication, displacement of TPs from binding proteins, modulation of Fcγ receptor expression, and others. The purpose of this review is to introduce the approach used by Pfizer scientists for evaluation of the DDI potential of novel TP products during drug discovery and development.
authors.affiliation: Pfizer Worldwide Research and Development, San Diego, CA 92121, USA. eugenia.kraynov@pfizer.com
authors.forename: Eugenia
authors.initials: E
authors.lastname: Kraynov
authors.forename: Steven W
authors.initials: SW
authors.lastname: Martin
authors.forename: Susan
authors.initials: S
authors.lastname: Hurst
authors.forename: Odette A
authors.initials: OA
authors.lastname: Fahmi
authors.forename: Martin
authors.initials: M
authors.lastname: Dowty
authors.forename: Carol
authors.initials: C
authors.lastname: Cronenberger
authors.forename: Cho-Ming
authors.initials: CM
authors.lastname: Loi
authors.forename: Bing
authors.initials: B
authors.lastname: Kuang
authors.forename: Owen
authors.initials: O
authors.lastname: Fields
authors.forename: Scott
authors.initials: S
authors.lastname: Fountain
authors.forename: Michel
authors.initials: M
authors.lastname: Awwad
authors.forename: Diane
authors.initials: D
authors.lastname: Wang
mesh_terms: D001688:Biological Products / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011506:Proteins / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D001688:Biological Products; D004364:Pharmaceutical Preparations; D011506:Proteins