Assessment of non-linear combination effect terms for drug–drug interactions

• Published in: Journal of Pharmacokinetics and Pharmacodynamics Vol. 43; no. 5; pp. 461 - 479
• Main Authors: Koch, Gilbert, Schropp, Johannes, Jusko, William J.
• Format: Journal Article Book Review
• Language: English
• Published: New York Springer US 01.10.2016; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Computer Simulation; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Humans; Kinetics; Models, Biological; Nonlinear Dynamics; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - metabolism; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Protein Binding; Receptors, Drug - metabolism; Review Paper; Veterinary Medicine/Veterinary Science; Loewe Additivity; Optimal concentration; Combination therapy; Bliss Independence; Drug–drug interaction
• ISSN: 1567-567X; 1573-8744
• DOI: 10.1007/s10928-016-9490-0

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.