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

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The Issue

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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

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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.

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What are sister chromatid exchanges (SCE)?

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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.

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What are chromosomal aberrations?

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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.

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What are micronuclei?

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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

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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).

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Data summary from El-Zein et al.

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Data summary from El-Zein et al.

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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

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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

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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.

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Effect of preparation quality on SCE frequencies

Good preparation Bad preparation

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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

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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

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