Precision Prescription by Paula A. Kiberstis
Physicians have long recognized that a therapeutic drug eliciting the desired response in one patient (maximal efficacy for the disorder being treated, with minimal side effects) may achieve only a suboptimal response in another patient. Because genetic differences can contribute to variation across individuals in drug responsiveness, there is growing interest in the idea that gene-based or pharmacogenomic tests might allow a better matching of drugs and drug dosages to individual patients.
Progress along these lines is described by three independent groups that have studied the drug clopidogrel, an inhibitor of blood clots that is commonly prescribed for patients after a heart attack in order to reduce the chance of subsequent coronary events. Clopidogrel is a pro-drug and is inactive until it is metabolized in the liver by cytochrome P450 enzymes, including CYP2C19. In two large studies involving 1500 to 2200 clopidogrel-treated patients who were monitored for 12 to 15 months, Mega et al. and Simon et al. found that individuals who carried one or two variant alleles of CYP2C19 that confer loss of enzyme function were 1.5 to 3.5 times more likely to die or experience cardiovascular-related complications than patients who carried high-functioning alleles. Collet et al. reported broadly similar results in a smaller study of 250 clopidogrel-treated patients who had suffered a heart attack at a young age. The consistency of the outcomes seen in these studies is promising and may set the stage for a prospective clinical trial designed to assess whether CYP2C19 genotyping would add a new chapter to the physician's pharmacopoeia.
New Engl. J. Med. 360, 354; 363 (2009); Lancet 373, 309 (2009).
Physicians have long recognized that a therapeutic drug eliciting the desired response in one patient (maximal efficacy for the disorder being treated, with minimal side effects) may achieve only a suboptimal response in another patient. Because genetic differences can contribute to variation across individuals in drug responsiveness, there is growing interest in the idea that gene-based or pharmacogenomic tests might allow a better matching of drugs and drug dosages to individual patients.
Progress along these lines is described by three independent groups that have studied the drug clopidogrel, an inhibitor of blood clots that is commonly prescribed for patients after a heart attack in order to reduce the chance of subsequent coronary events. Clopidogrel is a pro-drug and is inactive until it is metabolized in the liver by cytochrome P450 enzymes, including CYP2C19. In two large studies involving 1500 to 2200 clopidogrel-treated patients who were monitored for 12 to 15 months, Mega et al. and Simon et al. found that individuals who carried one or two variant alleles of CYP2C19 that confer loss of enzyme function were 1.5 to 3.5 times more likely to die or experience cardiovascular-related complications than patients who carried high-functioning alleles. Collet et al. reported broadly similar results in a smaller study of 250 clopidogrel-treated patients who had suffered a heart attack at a young age. The consistency of the outcomes seen in these studies is promising and may set the stage for a prospective clinical trial designed to assess whether CYP2C19 genotyping would add a new chapter to the physician's pharmacopoeia.
New Engl. J. Med. 360, 354; 363 (2009); Lancet 373, 309 (2009).
