The Need to Establish a Common Base Line for the Characteristics of Safety Withdrawal of Prescription Drugs from Worldwide Pharmaceutical Markets

Abstract

So often at conferences or in introductions to papers certain facts are stated that headline the dangers of pharmaceutical agents and why certain areas of work should be prioritised. Such statements are useful, but only if they are well researched and their validity as can be established. If not they become under-researched dogma, which unfortunately gains status simply by its repetition. This editorial is a plea to toxicologists, clinical pharmacologists and drug metabolism scientists to try to establish a documented link to primary literature material. Similarly when research is conducted in these areas certain controls and conditions are applied. Typically hepatotoxicity is spoken of as the major cause of drug withdrawal without further qualification and with little reference to other causes. This is often the opening remark to an experimental in vitro test for hepatic effects. The most cited reference is that of Fung et al (1) dealing with the period 1960-1999. Periods are important, as the availability of several drugs (e.g. non selective, and selective cyclo-oxygenase inhibitors) in a class allow comparisons concerning safety, often leading to withdrawal of the one(s) or more with the worst benefit-risk. This statement leads the reader in two ways highlighted in italics. (i) If hepatotoxicity is the major cause, all others are minor. Since 1980 to date, 24 drugs have been withdrawn from the US market with 6 drugs (25%) due to hepatotoxicity (2). In contrast 5 drugs have been withdrawn due to effects of their primary target pharmacology and 8 drugs due to off target pharmacology against. recognised receptors or enzymes. Interactions with the IKr channel account for 4 (50%) of this subclass. Perhaps the headline statement should be “of the reasons for the safety failure of pharmaceutical agents hepatotoxicity is the area we have made the smallest impact numerically and scientifically”. (ii) Hepatotoxicity is a black or white characteristic of a drug. Screens and other in vitro experiments can therefore compare a series of drugs and look for signals from the hepatotoxic ones. Exceeding the physiological concentrations by many orders of magnitude is permissible, if the output discriminates good from bad. In fact almost all drugs can be linked to some degree of hepatic toxicity. A recent review cites over 1000 hepatotoxic drugs (3). The incidence of hepatotoxicity correlates to some degree with the number of patients prescribed the drugs, somewhat confounding simple analysis. Moreover, studies of individual drugs or classes of drugs show a high variation due to the low incidence of, toxicity. For instance, controlled-cohort studies (4) have shown Ibuprofen (44.6/100,000 patient years) to have a higher incidence of liver disease (defined as >2XULN in liver clinical chemistry) than diclofenac (22.7/100,000 patient years). This is contrary to the widely perceived view and contrary to other reports. For actual withdrawn drugs, those withdrawn tend to show a higher incidence than comparable agents, but others in the class are usually not devoid of toxicity. Because of their relatively rare nature, the random generation of a series of findings relatively close together can be influential in the withdrawal of a drug and explain inter-country differences. As an example, most antidepressants are not normally judged as hepatotoxic, nevertheless cases are reported at 1.28 to 4.00 cases per 100,000 patient years. Copyright © 2008 by School of Pharmacy Shaheed Beheshti University of Medical Sciences and Health Services Iranian Journal of Pharmaceutical Research (2008), 7 (4): 233-235