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Editorial
The personalized medicine revolution:Getting it right for children
The Personalized Medicine Revolution will comeslowly. The fact that it is a revolution is certainlyno longer in doubt, but that does not help easeour impatience. The fundamental practice ofmedicine and the way in which we approach thetreatment of diseases will be forever altered.Understanding a disease process at the mostbasic level in an individual patient and then beingable to act on that information will be aremarkable change. No longer will mere symp-tomatic appeasement of the disease process benecessary.But do not expect this to happen this year, or
even in this decade. As Dr. Lawrence Lesko,former Director of the FDA�s Office of ClinicalPharmacology, frequently stated, the Personal-ized Medicine Revolution is a process no lesssignificant and with no shorter time requirementthan the Industrial Revolution. The IndustrialRevolution transformed society as we know it,but it took 80 yr to do so. During the timefollowing the Industrial Revolution, the world�spopulation increased sixfold because of anincreased standard of living. Given the transfor-mation in drug development and medical prac-tice that we expect to occur, it is only fair toassume that the Personalized Medicine Revolu-tion will continue to change medical practiceduring most of the 21st century.Why should the Personalized Medicine Revo-
lution take that long? We all had high expecta-tions immediately following the Human GenomeProject completion. If we know the humangenome, how difficult can it be to apply thatinformation to disease processes and their treat-ment? Fig. 1 is an oversimplified version of thecomplex process that we will have to decipher.The parts, which we often employ as biomarkersof drug response, continually change in relationto changes in other parts, so our measurementsof proteins, metabolites, epigenomics, andmRNA are simply a snapshot in time of a
dynamic process. We have to understand thethousands of working parts first, and figure outhow each part changes when put into a newenvironment.Then what is the significance of a study of
polymorphisms in CYP3A5 in 48 children fol-lowing renal transplantation conducted by Ferr-aris et al. (1) and described in this issue? I suggestthat you think of this as a puzzle with millions ofpieces. Each piece of information that we get maybe just a fraction of a piece, but contributes toour overall understanding of the entire system.Given this analogy, we should not ignore anysmall part of a piece of the puzzle, especially forpediatric patients in whom we have so littlebiomarker information.At the same time, we should not overinterpret
the findings of such a small study. There is noreason presently to genotype CYP3A5 in everychild undergoing solid organ transplantation,especially when we have assays and therapeuticdrug monitoring for the majority of the mainimmunosuppressant drugs. Pharmacogenomicsand therapeutic drug monitoring should becomplimentary (2). For most chronically admin-istered drugs today, monitoring blood or plasmaconcentrations provides much better insight intothe use of the drug in an individual patient thandoes any analysis of a single nucleotide poly-morphism.Ferraris et al. did attempt to investigate the
developmental aspect of CYP3A5 polymorphismsin this pediatric renal transplant population.While the number of patients was small, theydid examine the tacrolimus dose and dose-nor-malized trough blood concentrations in prepu-bertal and pubertal patients. As expected,CYP3A5 polymorphisms did not play a role indifferences in drug doses between these twogroups. Future studies of developmentalpharmacogenomics should focus on periods ofmaturation of the drug metabolizing enzyme of
Pediatr Transplantation 2012 Published 2012. This article is a U.S. Government work and is in the public domain in the USA.
Pediatric TransplantationDOI: 10.1111/j.1399-3046.2011.01638.x
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interest, which generally involves studying ade-quate numbers of much younger children.We should carefully examine each of the pieces
of new biomarker information that we get.Sometimes, even a few pieces of the puzzle cancome together to make a clearly identifiablepicture. That is the case with the hypersensitivityreaction to the antiviral drug abacavir, as relatedto the HLA-B*5701 allele. As now contained inthe FDA-approved label, testing for the HLA-B*5701 allele and avoiding the drug in patientswho test positive has produced a dramatic dropin the rate of hypersensitivity reactions becauseof abacavir (3). We will eventually understandthe molecular basis for this association, but fornow the clinical utility of HLA-B*5701 testinghas been confirmed and warrants inclusion in theFDA-approved label.As you might expect in year 10 of an 80-yr
process, other pieces of the puzzle give us a veryincomplete picture. Can we predict ototoxicity inchildren with malignancies who are treated withcisplatin by testing for genotypes of TPMT, assuggested by a recent study (4)? Genetic testingappears in this study to provide a significantlikelihood of identifying those children who willbe affected, potentially enabling practitioners tomake adjustments in monitoring strategies andintervene earlier to allow these children to lead abetter life. However, there presently is no provenbiologically plausible reason why TPMT poly-morphisms should affect cisplatin disposition ortoxicity. It is hoped that additional studies willfill in pieces of the puzzle and allow us to see thissection clearly.Following solid organ transplantation in chil-
dren, drug therapy response and toxicity are
poorly predictable. Donor–recipient match,immunologic polymorphisms, and pharmacoge-netic factors all may influence the final outcome.The collection of the pieces has come throughintensive studies of tissue matching, cytokinepolymorphisms, and polymorphisms of multipleenzymes and transporters which influence immu-nosuppressant disposition. The list of thosefactors and the studies that have been performedover the past two decades are too numerous tolist in this brief commentary, but in spite of this,all of the pieces do not create a clear picture ofhow these factors can be used to improve theoutcomes of children undergoing organ trans-plantation.Who will perform the studies that fill in the
pieces of the puzzle and allow us to accuratelypersonalize a medical treatment or immunosup-pressant plan? The academic community is veryinvolved (5). In the area of transplantation, aseries of national and international meetings nowfocus on biomarkers in transplantation. Phar-maceutical manufacturers could play a largerrole as they determine how to fold personalizedmedicine into drug development. One recentFDA guidance deals with the early incorporationof pharmacogenomics during drug development,and those studies could increasingly provide thetools for personalized treatment decisions (6).Incorporating a medical innovation into clinicalpractice also brings its own unique challenges (7).While the time course of integration of phar-
macogenomic and other biomarker informationinto pediatric medical practice is unknown, thePersonalized Medicine Revolution has startedand will continue over the next several decades.Progress is expected to be slow at first, but we
Fig. 1. Depiction of the complex interplay of proteomics, metabolomics, transcriptomics, epigenomics, and pharmacoge-netics in any one individual patient. The timeline indicates that each measurement is just a snapshot in time. Our completionof the puzzle for each disease will require sequential measurements in thousands of patients along with all of the informationthat comprises a patient�s phenotype.
Editorial
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should continually look for opportunities to see asection of the puzzle clearly and when warranted,apply that section to improving the care ofpediatric patients. We should not be tempted toprematurely utilize this information in patientcare, because this would only do a disservice topatients and to the progress of personalizedmedicine. We should make sure that we get itright for our pediatric patients.
Disclaimer
The opinions expressed in this commentary are those of theauthors and should not be interpreted as the position of theU.S. Food and Drug Administration.
Gilbert J. Burckart and Dionna J. Green
Office of Clinical Pharmacology, Office of Translational
Sciences, U.S. Food and Drug Administration,
Silver Spring, MD, USA
E-mail: [email protected]
References
1. Ferraris JR, Argibay PF, Costa L, et al. Influence of
CYP3A5 polymorphism on tacrolimus maintenance doses and
serum levels after renal transplantation: Age dependency and
pharmacological interaction with steroids. Pediatr Transplant
2011: 15: 525–532.
2. Burckart GJ, Liu XI. Pharmacogenetics in transplant patients:
Can it predict pharmacokinetics and pharmacodynamics? Ther
Drug Monit 2006: 28: 23–30.
3. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening
for hypersensitivity to abacavir. N Engl J Med 2008: 358: 568–
579.
4. Ross CJD, Katzov-Eckert H, Dube M-P, et al. Genetic vari-
ants in TPMT and COMT are associated with hearing loss in
children receiving cisplatin chemotherapy. Nat Genet 2009: 41:
1345–1349.
5. Sarwal MM, Benjamin J, Butte AJ, et al. Transplantomics
and biomarkers in organ transplantation: A report from the first
international conference. Transplantation 2011: 91: 379–382.
6. U.S. Food and Drug Administration. Guidance for Industry:
Clinical Pharmacogenomics: Premarketing Evaluation in Early
Phase Clinical Studies, 2011. Available at: http://www.fda.gov/
downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM243702.pdf (accessed December 16, 2011).
7. Burckart GJ, Frueh FW, Lesko LJ. Progress in the direct
application of pharmacogenomics to patient care: Sustaining
innovation. J Appl Pharmacol, 2007: 15: 1–6.
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