Integration of Immunotoxicology Evaluation in Drug Development
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0092-8615197 Copyright 0 1997 Drug Information Association Inc.
INTEGRATION OF IMMUNOTOXICOLOGY EVALUATION IN DRUG DEVELOPMENT JACK H. DEAN Sanofi Research, Sanofi Pharmaceuticals,Inc., Malvem Pennsylvania
BERNARD REMANDET Sanofi Recherche, Montpellier, France
During the past 20 years, significant progress has occurred in the fields of basic and clinical immunology which has provided newec more sensitive methods to assess immune system effects following exposure to chemicals or drugs in humans and laboratory animals. Methods have been selected, optimized, and validated with reference compounds in rodents through several interlaboratory collaborative studies to evaluate the predictive value for detecting toxicity for the immune system of new chemicals and drug candidates. The approach at Sanofi with the evaluation and application of immunotoxicity methods to the preclinical development of new chemical entities (NCEs)(eg, 21 compounds examined) as well as with reference compounds (dexamethasone, cyclophosphamide, and cyclosporin A ) is provided. The experience at Sanofi has led researchers there to believe that immunotoxicity endpoints represent another important aspect of safety assessment, can be integrated easily into the drug development process, do not yield a high rate of false positive results, and can be applied on an as needed basis. These evaluations can be driven by data suggestive of an immune effect, the drug’s indication, and the class of the chemical being evaluated (eg, anti-AIDS NCE) or systematically performed. Key Words: Drug development; Immunotoxicity; Dexamethasone; Cyclophosphamide; Azathioprine; Cyclosporine A
INTRODUCTION DURING THE PAST 20 years, significant progress has occurred in many fields including basicklinical immunology which has provided newer methods that have been standardized for clinical use, evaluated, and applied to product safety testing in rodents. The Presented at the DIA Workshop “Immunotoxicity of Pharmaceuticals: Current Knowledge, Testing Strategies, Risk Evaluation & Consequences for Human Health,” October 2 4 , 1996, Montreux, Switzerland. Reprint address: Dr. Jack Dean, Diplomate A.B.T., President and Scientific Director, Sanofi Research, Sanofi Winthrop, Inc., 9 Great Valley Parkway, P.O. Box 3026, Malvem, PA 19355.
interest in the application of the basic science and testing methods of immunology among toxicologists led to the establishment of several international interlaboratory validation studies of these methods in rodents using compounds with known immunotoxicity. Likewise, the topic has spawned numerous symposia and national and international toxicology meetings including the second Drug Information Association workshop on immunotoxicology of pharmaceuticals. In spite of significant interest among toxicologists, only minimal progress has been made in introducing immunotoxicity methods into routine safety assessment because of considerable uncertainties over relevance of rodent find-
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