Personalized medicine evolving into precision medicine
J. Steven Leeder , Pharm.D., Ph.D. and Richard L.Gorman, M.D., FAAP
Focus on Subspecialties
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
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 isMarion 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.