Strategies to Minimize Adverse Outcomes From Unintended DDIs

Sheldon H. Preskorn, MD

David Flockhart, MD, PhD

Dr. Preskorn is Professor, Chair, Department of Psychiatry and Behavioral Sciences, University of Kansas Shool of Medicine, CEO, Clinical Research Institute

Dr. Flockhart is Professor of Medicine, Genetics, and Pharmacology; Chief, Division of Clinical Pharmacology, Indiana University School of Medicine

DDIs are always determined by the pharma-codynamics and pharmacokinetics of the co-prescribed drugs. The following two equations are essential to understanding and avoiding DDIs:

Equation 1

Equation 2

Equation 1 presents the three variables that determine the effect a drug will produce in a patient. First, the drug must work on a site of action (the first variable in Equation 1) that is capable of producing the effect observed. For all drugs, except anti-infectives, the site of action is a human regulatory protein such as a receptor, an enzyme, or an uptake pump. The ability of the drug to bind to the regulatory protein gives it its potential action (ie, its pharmacodynamics). For the drug to express its potential action, it must reach the target to a sufficient degree to engage it to a physiologically relevant extent. That is the domain of the second variable in Equation 1. At low concentrations, the drug will bind to its most potent target. As the concentration increases, the drug will bind more substantially to that target until it is saturated. It will also begin binding to lower affinity targets when its concentration reaches a sufficiently high degree relative to its binding affinity for secondary targets.

Equation 2 illustrates that drug concentration is a function of the dosing rate the patient is taking relative to their ability to clear the drug. This equation explains why clearance is as important as dose in determining the nature, the magnitude, and the duration of a drug’s effect on the patient. The second variable in Equation 1 is the drug’s pharmacokinetics (or drug movement), which has four phases summarized by the acronym ADME: Absorption of the drug from the site of administration into the body, Distribution of the drug to the various compartments of the body, Metabolism or biotransformation into more polar substances, and finally, Elimination from the body. The last variable in Equation 1 is the interindividual differences among patients, which can shift the dose-response curve making patients either more or less sensitive to the effect of the drug. These differences are summarized by the acronym GADE: Genetics, Age, Disease, and Environment. The environment variable refers to the internal environment of the body, which includes other drugs or dietary substances the patient may be taking. These four variables modify the first two variables and, thus, explain how the magnitude, duration, or even the nature of the effect of the drug in a specific patient may differ from the usual effect produced by a given dose of the same drug.

Disclosure: Dr. Preskorn is a consultant to Bristol-Myers Squibb, Cyberonics, Eli Lilly, Johnson&Johnson, Memory, Otsuka, Pfizer, Shire, Somerset, and Wyeth; is on the speaker’s bureaus of Bristol-Myers Squibb, Cyberonics, Forest, Otsuka, and Pfizer; and receives grant support from Brtistol-Myers Squibb, Cyberonics, Johnson&Johnson, Memory, Merck, The National Institute of Mental Health, Novartis, Organon, Otsuka, Pfizer, Predix, Sepracor, and Somerset.

Disclosure: Dr. Flockhart is a consultant to Hoffman-La-Roche.