Quantitative and Systems Pharmacology Approach to Personalizing Therapy
Michael Maitland, MD, Schar Cancer Institute, Inova Health System, Annandale, Virginia, USA
Authored by Christopher Nabel
In the new era of cancer treatment—highlighted by targeted therapies and immune checkpoint blockade—the immune correlates of response and on-target versus off-target mechanisms of resistance dominate the conversations about our therapeutic agents. Under the bright lights of these newer areas of cancer biology, the study of pharmacology may not receive as much attention, yet it remains as pertinent as ever. Particularly for this reason, I greatly appreciated Dr. Maitland’s talk and perspective on this topic. His talk started with a brief summary of the differences between pharmacokinetics and pharmacodynamics, reviewing key concepts such as absorption/distribution/metabolism/excretion of drugs as well as the lag-time, Cmax/Tmax, and half-life associated with drug levels. From there, he transitioned to addressing how we think about inter-individual variability with regards to drug responses. This area is especially thought-provoking, and it feels particularly absent from the overall narrative regarding whether a patient will respond to a targeted therapy. How does one account for this inter-individual variability, particularly in an era where our focus on genetic sequencing is skewed towards somatic mutational profiling and away from germline polymorphisms that affect drug metabolism?
As an illustration of this point, we walked through the therapeutic index of targeted therapies. Broadly speaking, at a given dose of drug, the therapeutic window is defined by the difference between the clinical efficacy of the drug and the toxicity of associated side effects. When we perform clinical trials, we aggregate this information across a large population to obtain metrics on progression-free and overall survival, contrasted with adverse events; however, the therapeutic index across a population may not accurately predict the therapeutic index for a given, individual patient. VEGF targeted therapies provide an example of this concept, where ambulatory blood pressure monitoring can provide quantification of the inter-individual variability of treatment-related hypertension, and suggest a possible biomarker for increased risk of toxicity with treatment. As a further example of this point, specifically with the goal of making actionable decisions that affect patient care, Dr. Maitland presented the interesting case of a morbidly obese patient he treated with platinum-based chemotherapy. After the patient received a first round of cisplatin treatment, ensuing renal failure further complicated the administration of an excessive dose of carboplatin. The patient ultimately experienced a severe thrombocytopenia. However, using the degree of thrombocytopenia to correct the chemotherapy dosing based on degree of this toxicity, Dr. Maitland was able to identify correct dosing that ultimately allowed the patient to receive a safe and effective dose of treatment, resulting in a positive response to treatment.
What should one take away from this talk, and what lessons can be learned moving forward? I was most impressed by the thoughtful consideration of why patients develop the adverse reactions. Rather than accept these toxicities at face value, Dr. Maitland’s insights challenge us to apply the fundamentals of clinical pharmacology to try to understand the basis for the variable responses that we see, with the ultimate goal that these insights may allow us to apply additional knowledge about the drug to meaningfully improve patient outcomes.
Authored by Makoto Nishino
Starting from an interesting but important trivia question, Dr. Maitland’s lecture focused on pharmacogenomics. With the progress in genome sequencing technology, cost per human genome has fallen from $ 100,000,000 in 2001 to $1,000 in 2019. This change made for easier access for genome sequencing by reducing cost, enabling risk prediction, and bringing personalized preventive medicine into reality. On the other hand, fundamental issues such as smoking cessation, adequate exercise, and a Mediterranean diet are still important. Moreover, the academic area of pharmacogenomics has become more important. Citing the Nature review of a drug discovery article by Dr. Fitzgerald, individualized medicine can be taken into reality thanks to the collaboration of pharmacology and genomics.
Clinical pharmacology is known as a science of understanding inter-individual differences in drug metabolism and response and implementation of that knowledge to improve the safety and efficacy of therapeutics. Pharmacokinetics is known to consist of four parts; absorption, distribution, metabolism, and elimination. A fundamental concept of clinical pharmacology is the therapeutic index. Good drugs provide the patient and the prescriber with flexibility in dosage that achieves treatment benefits without incurring significant toxicity. The blockade of angiogenesis during the right phase of disease, for example, is expected to have a wide therapeutic index. But we’ve developed these drugs largely in the metastatic disease setting where clinical efficacy is low, and then carried forward the one-size-fits-all dosing program into the adjuvant setting, where our tolerance for toxicity is lower than in the metastatic setting. It is important to focus on the therapeutic index in order to maximize the outcome for the individual patient care. Another example demonstrated was fluorouracil, that first found familial deficiency of the lower cascade of 5-FU metabolism; later SNPs was found, and a scoring system was made thanks to clinical pharmacogenetics development.
It used to be that it took a lot of time for a medicine to become FDA-approved through the classic basic research-drug discovery-preclinical-Phase1-Phase2-Phase3 sequence; these days there is a changing paradigm that is Phase 0 for pharmacodynamics evaluation, phase1a for safety dose finding, Phase1b known as dose expansion that looks for activity in specific population, often biomarker-selected, Phase2 for randomization and achieving accelerated approval, post marketing commitment, and requirement for safety. This change means intense and competitive racing will take place, with less patient recruitment, new safety challenges, and new demands for companion diagnosis technology. In Japan, NGS paneling testing is now reimbursed by the government, and there are growing needs toward pharmacogenomics and clinical pharmacology in Japan too.
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