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Cytogenetic Effects of Methylphenidate Pediatric Advisory Committee

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.

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Cytogenetic Effects of Methylphenidate Pediatric Advisory Committee

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  1. Cytogenetic Effects of MethylphenidatePediatric 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

  2. The Issue

  3. Study design • Examined three endpoints in 12 children diagnosed with ADHD. Blood drawn before and after 3 month treatment with methylphenidate. • Sister chromatid exchange • Chromosomal aberrations • Micronuclei • Therapeutic doses were 20 to 54 mg/day

  4. 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.

  5. What are sister chromatid exchanges (SCE)?

  6. 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.

  7. What are chromosomal aberrations?

  8. 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.

  9. What are micronuclei?

  10. 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

  11. 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).

  12. Data summary from El-Zein et al.

  13. Data summary from El-Zein et al.

  14. Questions Regarding El-Zein Study • Lack of placebo controls • Use of unusual data presentation • Aberrations/cell instead of % damaged cells • Total SCE in 25 cells • Presence of 6 subjects with 0 SCE/cell • Investigators agreed to a site visit to answer questions

  15. Site visit to Univ. of Texas • Representatives from NIEHS, NICHD, FDA and EPA site visited U of T on May 23rd. • Reviewed: • Patient selection • Methods • Raw data • Slide evaluation

  16. 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.

  17. Effect of preparation quality on SCE frequencies Good preparation Bad preparation

  18. 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

  19. 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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