Can Pharmacogenetics Help Rescue Drugs Withdrawn from the Market?

Abstract

Observations over the later half of the last century have suggested that genetic factors may be the prime determinant of drug response, at least for some drugs. Retrospectively gathered data have provided further support to the notion that genotype-based prescribing will improve the overall efficacy rates and minimize adverse drug reactions (ADRs), making personalized medicine a reality. During the last 16 years, 38 drugs have been withdrawn from major markets due to safety concerns. Inevitably, a question arises as to whether it might be possible to 'rescue' some of these drugs by promoting genotype-based prescribing. However, ironically pharmacogenetics has not perceptibly improved the risk/benefit of a large number of genetically susceptible drugs that are already in wide clinical use and are associated with serious ADRs. Drug-induced hepatotoxicity and QT interval prolongation (with or without torsade de pointes) account for 24 (63%) of these 38 drug withdrawals. In terms of the number of drugs implicated, both these toxicities are on the increase. Many others have had to be withdrawn due to their inappropriate use. This paper discusses the criteria that a drug would need to fulfill, and summarizes the likely regulatory requirements, before its pharmacogenetic rescue can be considered to be realistic. One drug that fulfils these criteria is perhexiline (withdrawn worldwide in 1988) and is discussed in some detail. For the majority of these 38 drugs there are, at present, no candidates for genetic traits to which the toxicity that led to their withdrawal may be linked. For a few other drugs where a potential candidate for a genetic trait might explain the toxicity of concern, the majority of patients who experienced the index toxicity had easily managed nongenetic risk factors. It may be possible to rescue these drugs simply by careful attention to their dose, interaction potential and prescribing patterns, but without the need for any pharmacogenetic test. In addition, the pharmacogenetic rescue of drugs might not be as effective as anticipated as hardly any pharmacogenetic test is known to have the required test efficiency to promote individualized therapy. Multiple pathways of drug elimination, contribution to toxicity by metabolites as well as the parent drug, gene-gene interactions, multiple mechanisms of toxicity and inadequate characterization of phenotype account for this lack of highly predictive tests. The clinical use of tests that lack the required efficiency carries the risks of over- or under-dosing some patients, denying the drug to others and decreasing physician vigilance of patients. Above all, at present, prescribing physicians lack an adequate understanding of pharmacogenetics and its limitations. It is also questionable whether their prescribing will comply with the requirements for pretreatment pharmacogenetic tests to make pharmacogenetic rescue a realistic goal.