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Personalized medicine evolving into precision medicine :

December 27, 2016

Precision medicine is a much bandied about term. During his 2015 State of the Union address, President Barack Obama launched a precision medicine initiative “to bring us closer to curing diseases like cancer and diabetes.”

Precision medicine is a model that is not very different from personalized medicine. Both stress that therapeutic and treatment decisions are based on information about an individual. What continues to evolve is the amount of diagnostic and individual information that is available.

The rapid development of genomics, proteomics, metabolomics, cellular assays, diagnostic radiology and diagnostic sonography is a potential game changer in individual care. The ability to analyze large data sets at the population level and apply results to an individual patient also is evolving rapidly.

The concept of precision medicine is not new to pediatricians. The treatment of infections was based on symptoms, readily available lab results (white blood cell counts, erythrocyte sedimentation rate, C-reactive protein), patient age, likely organisms and potential outcomes of both the disease and the therapy. Treatment became more precise with better diagnostics such as gram stains, cultures and sensitivities. Similarly, the ability to measure blood types and Rhesus factors enabled blood transfusion to become more individualized, safer and more effective.

The same tools transforming personalized medicine to precision medicine are transforming pharmacokinetic thinking and research. In the clinical arena, the question asked is “What dose should we give?” In the pharmacokinetic arena, the answer is “What response do you want?” Linking the clinical question and pharmacokinetic answer is the concept of how much drug needs to be in the body — the “systemic exposure” — to elicit the desired response.

Working back from the desired response and the exposure required to elicit that response, drug developers and pharmacokineticists can devise the correct dose to achieve the exposure based on a patient’s individual characteristics. Information needed to predict and measure the responses to therapeutic agents includes things that pediatricians are aware of such as age and weight. However, the next level of understanding requires knowledge of drug absorption, changes in expression of drug metabolism enzymes during growth and development, and the developmental trajectory of the drug target itself.

A simple example is the metabolism of ethyl alcohol by children. Infants are born with approximately 10% of an average adult’s ability to metabolize alcohol. By 2 years of age, the ability reaches only about 30% of the adult ability. The recognition of the development of alcohol dehydrogenases ontogeny led to the removal of alcohol from virtually all pediatric medications.

In addition to genomics, proteomic, metabolomics and the like, pediatric pharmacologists and drug developers need to deal with the ontogeny of both the metabolic pathway and the drug target. Pediatricians have been practicing personalized or precision medicine for generations by dosing drugs in terms of milligrams of drug per kilograms of weight. However, to get to the next level of rational drug use, pediatricians need to become familiar with projects like the GOLDILOKs Project at Children’s Mercy Hospital in Kansas City, Mo.

The project starts with the desired response, taking into account the variables mentioned above to model and project the optimal dose for a specific pediatric patient. Consider giving a “slow metabolizer” of an active drug one-tenth of the recommended dose or a “fast metabolizer” with a highly expressed drug target 20 times the recommended maximum dose. While pediatricians are comfortable with the “one size does not fit all” concept, old conventions will be difficult to shatter until they become comfortable with the data and science behind precision dosing of drugs.

Fortunately, such changes likely will be rolled out for drugs where metabolic pathways and drug targets are well-understood. Most likely, drugs with the highest therapeutic index (potential benefit/potential adverse event) will ease pediatric clinicians into this therapeutic tomorrow so they can provide the best possible care for their patients.


Dr. Leeder is Marion Merrell Dow/Missouri endowed chair in pediatric clinical pharmacology and director of the Division of Clinical Pharmacology and Therapeutic Innovation at Children’s Mercy, Kansas City. Dr. Gorman is interim chair of the AAP Section on Clinical Pharmacology and Therapeutics Executive Committee.

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