Individualizing therapy - in search of approaches to maximize the benefit of drug treatment (II)

Abstract

Adjusting drug therapy to the individual, a common approach in clinical practice, has evolved from 1) dose adjustments based on clinical effects to 2) dose adjustments made in response to drug levels and, more recently, to 3) dose adjustments based on deoxyribonucleic acid (DNA) sequencing of drug-metabolizing enzyme genes, suggesting a slow drug metabolism phenotype. This development dates back to the middle of the 20(th )century, when several different drugs were administered on the basis of individual plasma concentration measurements. Genetic control of drug metabolism was well established by the 1960s, and pharmakokinetic-based individualized therapy was in use by 1973.

Figure 1

Basic relationships. Net benefit is plotted as a function of outcome prevalence. The line represents the relationship with the assumption of a relative risk reduction of 30% and treatment harm of 0%. The line is the maximum net benefit that can be attained at any given outcome prevalence. The x-intercept, or benefit threshold, represents the outcome prevalence at which net benefit will accrue to individuals and the population as a whole. The point of maximum benefit occurs when the outcome prevalence is 100%; at this point, if harm is absent, the net benefit or efficiency of treatment equals the relative risk reduction or efficacy of that treatment. Benefit decreases proportionately as a function of outcome prevalence.

Figure 2

Exposure-response relationships. Relationships between (1) drug substance and drug product, (2) exposure expressed as dose or systemic exposure on log scale, and (3) positive (efficacy) or negative (toxicity) outcomes. These outcomes may be measured by clinical end points, surrogate endpoints, or biomarkers. The relationships between exposure and outcomes define the optimal dose and therapeutic window. The term change introduces the concept of equivalence in outcomes before or after a specified change (eg, generic substitution, postapproval manufacturing change). CMC, Chemistry, manufacturing, and controls; BA/BE, bioavailability and bioequivalence; PK, pharmacokinetics; PD, pharmacodynamics.