Individualization of Drug Therapy: History, Present State, and Opportunities for the Future

Abstract

Individualization of drug therapy, described as tailoring drug selection and drug dosing to a given patient, has been an objective of physicians and other health-care providers for centuries. An understanding of the pathogenesis of the disease, the mechanism of action of the drug, and exposure-response relationships provides the framework for individualization. There are many approaches to individualization: selecting an antibiotic based on minimum effective concentrations and bacterial sensitivity, population (sparse sample) pharmacokinetics, therapeutic drug monitoring and, more recently, pharmacogenomics. The goal of individualization is to optimize the efficacy of a drug, minimize its toxicity, or both. With the growth of technology and databases, drug-disease-trial models and simulation have become useful for integrating information from many different domains. Physiology-based pharmacokinetic (PBPK) models have provided a mechanistic approach to individualization, and clinical trial designs such as those involving enrichment have also enabled individualization. In the future, "-omics" technologies, vaccines, ex vivo gene therapy, and the so-called "diseases-in-a-dish" will provide additional strategies to achieve individualization.

Parameter estimation for sigmoid Emax models in exposure-response relationship

“…The approximate values of the T max (the time at which the maximum concentration was observed) for single-and multiple-dose study were 3.15 and 2.78 h, respectively and the half-life was around 13.9 h. The blood sampling time points for dense sampling schedules were 0 (predose), 0.25, 0.5, 0.75, 1,2,3,4,5,6,8,12,24, and 48 h after drug administration. The samples at 24 and 48 h were not included for multiple-dose scenarios.…”

“…[1] PK/PD modeling and simulation is also used for individualized pharmacotherapy based on relevant demographic factors including race, age, sex, weight, height and genotype. [4,5] Pharmacometric analysis usually relies on non-linear mixed effect models to explain and quantify time-varying PK/PD parameters, disease progression, and their relationships based on population data. Pharmacokinetic models describe the change of drug concentration over time and pharmacodynamic models quantify the relationship between concentration and effect.…”

Principles of Toxicology

“…The field as a whole benefits from such diversity and is thus always influx, which is probably best exemplified by the current use of the so-called omics technologies. These approaches, which might one day allow personalized clinical treatment, seek to examine patterns in an individual's macromolecular signature (e.g., the genome, transcriptome, or metabolome), and they rely heavily on the burgeoning field of computational biology, bioinformatics, and biostatistics to interpret their biomedical significance (Lesko and Schmidt, 2012).…”

Application and Utility of Pharmacogenetics in the Clinical Laboratory

“…Additionally, only a small percentage (5%) of molecular clinical laboratory testing is dedicated to SNP detection for PGx application [131]. These could be the case because the characterization of phenotype-genotype relationships were initially pursued to develop a personalized medicine approach to define a therapeutic window for drug dosage and optimize treatment success [29]. However, even though individuals can inherit (germline) or acquire (somatic) a genetic aberration, they may not necessarily exhibit the same phenotypic characteristics.…”

“…Although several polymorphisms result in aberrant enzyme activity, most variants are not associated with a particular phenotype, due to the fact that there is functional redundancy amongst the CYP drug-metabolizing enzymes [28]. However, genotypic characterization of germline polymorphisms in drug-metabolizing enzymes can play an important part in the phenotypic characterization of individuals who are poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), and ultra-rapid metabolizers (UM), for a particular substrate [29].…”