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The first effective immunosuppressive drug (ISD) was azathioprine, approved in 1968. Early experience with this drug suggested that patients might have an excess risk of tumors including lymphoma and skin tumors. Comparison among various registries has shown that the cumulative risk of tumors increases over time. The risk is additionally increased by the more intense immunosuppressive regimens needed for lung or heart-lung transplants. The link between immunosuppression and tumorigenesis was further reinforced by the high concordance of tumor types between transplant and HIV patients. The role of the immune system in tumor defense includes both direct tumor surveillance and immunity against oncogenic viruses. In transplant patients, at least two-thirds of the lymphomas are Epstein-Barr virus (EBV)–positive. Existing methods of testing for carcinogenicity are not considered adequate to identify the hazard of tumorigenesis due to these drugs. Research is ongoing in Food and Drug Administration laboratories and at collaborators’ laboratories to evaluate experimental systems that may have the ability to adequately identify this class of hazard. Initial work is on various model systems similar to EBV. These include the MHV-68 mouse model, lymphocryptovirus (LCV-1) in the cynomolgus monkey, and preliminary work with mice with humanized immune systems using EBV directly. [ABSTRACT FROM PUBLISHER]

Drug-induced phospholipidosis (PL) is a condition characterized by the accumulation of phospholipids and drug in lysosomes, and is found in a variety of tissue types. PL is frequently manifested in preclinical studies and may delay or prevent the development of pharmaceuticals. This report describes the construction of a database of PL findings in a variety of animal species and its use as a training data set for computational toxicology software. PL data and chemical structures were compiled from the published literature, existing pharmaceutical databases, and Food and Drug Administration (FDA) internal reports yielding a total of 583 compounds suitable for modeling. The database contained 190 (33%) positive drugs and 393 (77%) negative drugs, of which 39 were electron microscopy-confirmed negative compounds and 354 were classified as negatives due to the absence of positive reported data. Of the 190 positive findings, 76 were electron microscopy confirmed and 114 were considered positive based on other evidence. Quantitative structure-activity relationship (QSAR) models were constructed using two commercially available software programs, MC4PC and MDL-QSAR, and internal cross-validation (10 × 10%) experiments were performed to assess their predictive performance. Performance parameters for the MC4PC model were specificity 92%, sensitivity 50%, concordance 78%, positive predictivity 76%, and negative predictivity 78%. For MDL-QSAR, predictive performance was similar: specificity 80%, sensitivity 76%, concordance 79%, positive predictivity 65%, and negative predictivity 87%. By combining the output of the two QSAR programs, the overall predictive performance was vastly improved and sensitivity could be optimized to 81% without significant loss of specificity (79%). Many of the structural alerts and significant molecular descriptors obtained from the QSAR software were found to be associated with parts of active molecules known for their cationic amphiphilic drug (CAD) properties supporting the hypothesis that the endpoint of PL is statistically correlated with chemical structure. QSAR models can be useful tools for screening drug candidate molecules for potential PL. [ABSTRACT FROM AUTHOR]

The most commonly used assays designed to detect either skin or systemic immune-based hypersensitivity reactions are those using guinea pigs (GP). We obtained data from various FDA records to evaluate the correlation between GP assay results and reported post-marketing systemic hypersensitivity reactions. We examined the new drug application (NDA) reviews of approved drugs for the results of GP assays. Post-marketing human data were extracted from the FDA adverse event reporting system (AERS). Drug usage data were obtained from a commercial database maintained by IMS Health Inc. We found 83 (21%) of 396 drugs approved between 1978 and 1998 had reported GP test results. Among these 83 drugs, 14 (17%) were found to have positive results in at least one GP assay. Simple reporting index (RI) values for systemic hypersensitivity reactions were calculated from AERS data and usage to produce the index of adverse event reports per million shipping units of drug. A variety of definitions of positive human response were examined. A statistically significant association was seen for rash between post-marketing and clinical trials adverse event reports. No statistically significant associations between human data and GP test results were observed. These data suggest that standard GP assays have limited ability to predict human systemic hypersensitivity potential for pharmaceuticals. [Copyright &y& Elsevier]