Quantitative and Systems Pharmacology Approach to Personalizing Therapy
Michael Maitland, MD, PhD, Schar Cancer Institute, Inova Health System, Annandale, Virginia, USA
Authored by Jason Willis, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Complex human diseases are characterized by variability – that is, differences in disease risk, treatment response, tolerance, and outcomes amongst individuals in an affected population. As a complex disease, most adult-onset cancers have multiple sources of variability, including somatic, environmental, and heritable factors. Characterizing these factors is a major goal of precision clinical oncology.
Dr. Maitland’s talk outlined rigorous work over the past 5-10 years to better understand how germline (heritable) genetics factors contribute to disease variability. Particular focus is on the concept of pharmacogenetics – in which investigators have demonstrated that germline polymorphisms significantly alter drug pharmacokinetics, toxicity, or efficacy. The promise of quantitative and systems pharmacology is that the germline genetic information can be combined with other predictive information to ensure that the individual patient receives the intended systemic concentrations of an active drug. Dr. Maitland argued that we care more about adjusting the dose to achieve a general therapeutic range of plasma concentrations for each drug. Scientific investigations therefore are not about a specific type of biomarker or a single recommended phase 2 dose, but about achieving the best therapeutic index for each patient using all the clinical and laboratory tools reliably at our disposal.
As examples, Dr. Maitland first points to a landmark discovery by Diasio et al. (JCI 1988) of germline mutations in dihydropyrimidine dehydrogenase (DPD) that lead to significantly decreased metabolism and increased toxicity of 5-flurouracil. In the subsequent 30 years, testing for DYD deficiency has attempted but actually not useful in diagnostic guidelines for patients who have severe 5-FU toxicity. More recently pharmacologists have developed new ways to measure the achieved plasma concentrations of 5-FU metabolites and suggested that therapeutic drug monitoring (such as we use for dosing vancomycin) could be an effective way to personalize a 5-FU-based chemotherapy regimen. Another instructive example is the association of CYP2D6 metabolism status with side effects and efficacy of tamoxifen in adjuvant breast cancer therapy.