Chapter 14. Individualization of Drug Regimens: Integration of Pharmacokinetic and Pharmacogenetic Principles in Drug Therapy

Summary

Patients on drug therapy manifest different responses to the same regimen. A drug may have little or no therapeutic effects in some patients but elicit adverse effects at low doses in others. Interindividual variation in drug efficacy and safety has resulted in the failure of drug candidates in clinical trials and the withdrawal of other drugs from the market. Intersubject variation in drug response is thought to cost lives and dramatically increase healthcare costs. While matching the patient with the right drug and dosing regimen tailored to his or her therapeutic need would overcome these problems, efforts to use therapeutic drug concentration monitoring to individualize dosing have had limited clinical impact. With advances in medical genetics and the study of the genetic basis of variation in drug disposition and biologic activity (pharmacogenetics), some inter individual variability can be predicted. In such cases, the overall response to a drug is determined by variations in key proteins regulating disposition and activity. Application of pharmacogenetics in clinical practice is in its infancy, but there is every reason to think it will mature. Some unbridled enthusiasts believe that a day will come when each person carries a gene chip identification card, analogous to electronic IDs, or even an implanted chip, that contains complete genetic information, which can be used for therapeutic decision-making. The technical feasibility, however, must be matched by a paradigm shift in clinical practice and an acute sensitivity to ethical concerns before that day comes. As the study and application of pharmacogenetics matures, associations of genetic variations linked to therapeutic response need to be validated, and genotyping assays must be improved to be more “user friendly, ” (i.e., rapid, sensitive, reproducible, readily available, simple to use, and cost effective). As exemplified by the use of Herceptin, new drugs will increasingly be targeted to only some patients, those who display a particular genetic marker that critically influences efficacy and safety.