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Cytogenetic Effects of Methylphenidate Pediatric Advisory Committee. June 30, 2005 David Jacobson-Kram, Ph.D. DABT Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration. The Issue. Study design. - PowerPoint PPT Presentation
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Food and Drug
Administration
Cytogenetic Effects of Methylphenidate
Pediatric Advisory Committee
June 30, 2005David Jacobson-Kram, Ph.D. DABT
Office of New DrugsCenter for Drug Evaluation and Research
Food and Drug Administration
Food and Drug Administration
The Issue
Food and Drug Administration
Study design
Examined three endpoints in 12 children diagnosed with ADHD. Blood drawn before and after 3 month treatment with methylphenidate. Sister chromatid exchangeChromosomal aberrationsMicronuclei
Therapeutic doses were 20 to 54 mg/day
Food and Drug Administration
What are sister chromatid exchanges (SCE)?
Reciprocal exchanges of chromatid arms visualized in metaphase cells that have undergone two rounds of DNA replication in the presence of the nucleotide analogue bromodeoxyuridine.
While the mechanism of SCE is poorly understood, increases in their frequencies are generally indicative of DNA damage.
Food and Drug Administration
What are sister chromatid exchanges (SCE)?
Food and Drug Administration
What are chromosomal aberrations?
Chromosomal aberrations represent unrepaired or misrepaired chromosomal lesions that are visible under the light microscope.
The same processes that give rise to these events are associated with chromosomal alterations resulting in cancer, e.g. Burkitt’s lymphoma.
Food and Drug Administration
What are chromosomal aberrations?
Food and Drug Administration
What are micronuclei?
Micronuclei result from acentric chromosome fragments or whole chromosomes left behind in the cytoplasm after mitosis
They are visualized in binucleated cells that have been blocked for cytokinesis
Indicative of chromosome breakage or nondisjunction.
Food and Drug Administration
What are micronuclei?
Food and Drug Administration
What is the significance of these cytogenetic endpoints?
Chromosome aberration frequency in peripheral blood lymphocytes is an independent risk factor for cancer.*
If reproducible, data from the El-Zein paper suggest that patients taking methylphenidate may be at increased risk for cancer.
*Chromosomal aberrations and risk of cancer in humans: an epidemiologic perspective. Bonassi et al. 2004
Food and Drug Administration
What else is known about the mutagenicity/carcinogenicity of
methylphenidate? No structural alerts Metabolism qualitatively similar in humans and
animals but quantitative differences exist Negative in rat carc study and mouse p53 study Positive for liver tumors in mouse 2-year study Negative in Ames assay, mouse lymphoma gene
mutation assay and in vivo micronucleus test; some positive or equivocal results for in vitro chromosomal aberrations and SCE
Review of pharmacy and medical records of 143,574 patients found fewer cancer cases than expected (Selby et al., Cancer Res. 1989).
Food and Drug Administration
Data summary from El-Zein et al.
Food and Drug Administration
Data summary from El-Zein et al.
Food and Drug Administration
Questions Regarding El-Zein Study
Lack of placebo controls Use of unusual data presentation
Aberrations/cell instead of % damaged cellsTotal SCE in 25 cells
Presence of 6 subjects with 0 SCE/cell Investigators agreed to a site visit to
answer questions
Food and Drug Administration
Site visit to Univ. of Texas
Representatives from NIEHS, NICHD, FDA and EPA site visited U of T on May 23rd.
Reviewed:Patient selectionMethodsRaw dataSlide evaluation
Food and Drug Administration
Observations at site visit Investigators cordial, cooperative and
responded to all inquiries. Good concordance between raw data sheets
and data in publication. The slides were evaluated in a “blinded”
fashion but the same technician coded, evaluated and decoded slides.
A number of slides were chosen at random and were found to have low mitotic indices and poor differential staining for SCE.
Food and Drug Administration
Effect of preparation quality on SCE frequencies
Good preparation Bad preparation
Food and Drug Administration
Ongoing efforts to assess methylphenidate clastogenic
potential organized under BPCA El-Zein et al., are seeking funding to perform
larger (100 informative subjects) study NICHD, NIEHS and Duke are collaborating to
reproduce the El-Zein study CDC has developed a protocol for a cross-
sectional study that incorporates cytogenetic endpoints
NIMH will assess stable chromosomal rearrangements as part of an ongoing cross sectional study
Food and Drug Administration
Ongoing efforts to assess methylphenidate clastogenic potential
organized under BPCA
Division of Neuropharm drugs is asking IND holders to assess clastogenic potential
NCTR will perform experimental studies in non-human primates and transgenic mice
Other drugs used to treat ADD and ADHD will also be studied
First results will likely be available in about 1 year
Food and Drug Administration
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