title: Assessment of non-linear combination effect terms for drug-drug interactions.
abstract: Drugs interact with their targets in different ways. A diversity of modeling approaches exists to describe the combination effects of two drugs. We investigate several combination effect terms (CET) regarding their underlying mechanism based on drug-receptor binding kinetics, empirical and statistical summation principles and indirect response models. A list with properties is provided and the interrelationship of the CETs is analyzed. A method is presented to calculate the optimal drug concentration pair to produce the half-maximal combination effect. This work provides a comprehensive overview of typically applied CETs and should shed light into the question as to which CET is appropriate for application in pharmacokinetic/pharmacodynamic models to describe a specific drug-drug interaction mechanism.
authors.affiliation: Pediatric Pharmacology and Pharmacometrics, University of Basel, Children's Hospital (UKBB), Spitalstrasse 33, 4056, Basel, Switzerland. gilbert.koch@ukbb.ch.|Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA. gilbert.koch@ukbb.ch.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Koch
authors.affiliation: Department of Mathematics and Statistics, University of Konstanz, PO Box 195, 78457, Konstanz, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schropp
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D017711:Nonlinear Dynamics; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D010599:Pharmacokinetics; D011485:Protein Binding; D011955:Receptors, Drug / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D011955:Receptors, Drug
keywords: Bliss Independence; Combination therapy; Drug–drug interaction; Loewe Additivity; Optimal concentration