Assessment of Pharmacokinetic Drug Interactions in Clinical Drug Development

  • Jerome J. Schentag


Drug interactions of a minor nature occur commonly. They are often of little clinical consequence because one or both interacting drugs have wide therapeutic margins for both efficacy and safety. However, clinically significant adverse events do occur as a consequence of drug interactions in small subsets of patients, chiefly older patients with pre-existing organ dysfunction receiving interactants having narrow therapeutic windows. Although clinically rare, these few significant drug interactions have major impact on modern drug development and drug labeling stategies. In the course of registering a new drug, the pharmaceutical industry conducts many drug-drug interaction studies in normal volunteers, and even occasionally in patients. The first layer of these volunteer trials is part of late Phase II, and examines the kinetic interactions which would be anticipated from known relationships of the chemical classes or metabolic pathways. A “Check-list” approach is often followed. More and more frequently, these studies serve several purposes including molecular modification to produce new compounds without the potential for interaction, and competitive marketing. One major issue, seldom addressed, is whether the interactions tested in normal volunteers are subsequently found in patients. There is no assurance that a statistically significant pharmacokinetic interaction in volunteers will reliably predict a clinically significant interaction in patients. This observation led us to examine the degree of pharmacokinetic alteration which might predict a clinically detectable interaction. With a narrow therapeutic index drug like theophylline, we have found that clinical interactions are rarely detectable until the interacting agent reduces theophylline clearance by 40–50%. The magnitude of pharmacokinetic change may need to be even greater in order to anticipate clinical interactions between drugs with wider safety margins than theophylline.


Drug Interaction Normal Volunteer Narrow Therapeutic Window Pharmacokinetic Drug Interaction Theophylline Clearance 
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Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Jerome J. Schentag
    • 1
    • 2
  1. 1.Center for Clinical Pharmacy Research and Department of Pharmaceutics School of PharmacyState University of New York at BuffaloBuffaloUSA
  2. 2.The Clinical Pharmacokinetics LaboratoryMillard Fillmore HospitalBuffaloUSA

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