Anticipating Rather Than Confirming Drug Toxicity

To the Editor: Recently 1 of our potent arthritis therapies (leflunomide) made headlines because of deaths ascribed to liver toxicity. This resulted in calls for its withdrawal since the alleged deadly metabolite had a very long half-life. It was suggested that between the months of routine testing, irreversible liver toxicity, absent symptoms, silently led to death. Rather than just simply focusing on this 1 drug, I suggest we revisit the issue of how we presently attempt to safely monitor all of our potent drugs in arthritis therapy. Again, the irrefutable adage that those who ignore the past are condemned to relive the past applies. Several decades ago, benoxaprofen was introduced as a potent new nonsteroidal antiinflammatory drug (NSAID) to the arthritis marketplace. Within the year, a series of deaths were reported from this new agent. A long half-life glucuronide metabolite resulted in fatal liver toxicity, despite routine laboratory testing. At that time, it was clear that the glucuronide metabolite could be monitored, and the United States Food and Drug Administration did not request that this otherwise potent NSAID be withdrawn. But the company, in the face of a flurry of litigation, chose to withdraw it. In all of these subsequent years, it is common in the earliest phase of pharmacokinetic evaluation of new drugs to carefully delineate both metabolites and half-lives. To this we have added required pharmacokinetics testing during clinical research in subpopulations at risk, such as the very elderly. Yet despite the therapeutic toxicity risks of many of our potent agents, it is only recently that a clinical laboratory procedure for predicting efficacy and safety in routine practice has been commercially developed and available. In this case, it is for a drug long familiar to rheumatology, azathioprine. The initial clinical studies were in Crohn disease, with subsequent studies now continuing in rheumatoid arthritis. The genetic polymorphism of the enzymatic activity of 6-mercaptopurine measured as the enzymatic pathway of thiopurine methyltransferase can be distinguished prior to or at the time of initiating azathioprine. The homozygous alleles high metabolizer group ( 89%) with normal activity can be dosed according to calculated recommendations. However, the heterozygous alleles high/low metabolizer group ( 11%) has only intermediate enzyme activity with increased potential for toxicity at greater than limited dosing. However a homozygous alleles low metabolizer group ( 0.3%) should not receive azathioprine absent ability to metabolize the enzymatic pathway. Published studies include serodiagnostic testing of major metabolites, 6-thioguanine and 6-methyl-mercaptopurine that can subsequently be monitored after initiating therapy. Elevated 6-thioguanine levels have been statistically associated with bone marrow toxicity. Elevated 6-methyl-mercaptopurine levels are also associated with significant risk for hepatotoxicity. Reduced thiopurine methyltransferase activity associated with metabolic toxicity in methotrexate treatment of rheumatoid arthritis has been reported and definitive studies to further corroborate these observations are now nearing completion. A recent report of an unusual fatal outcome associated with methotrexate therapy once more raises the continuing concern for malignancy risks associated with long-term exposure to our most frequently used disease-modifying agents. Thus, specific concern here is directed to both methotrexate and a major metabolite (7-hydroxymethotrexate). The authors postulated that genotyping may have predictive value based upon studies in animal models. They also speculated that phenotyping of human leukocytic antigen DR4 may provide predictive direction to 386 Journal of CLINICAL RHEUMATOLOGY