HOME- R&D
- Bryn Mawr Conference
- Program & Schedule
- Location
- Screening Workshop
- Call for Contributions
- Bursary Awards
- Poster Session
- Sponsors & Exhibitors
- Program 2007
- ADMET
- Beger, R
- Cherkasov, A
- Contrera, J
- Helma, C
- Hopfinger, A
- Jamois, E
- Klon, A
- Madden, J
- Pelletier, D
- Poroikov, V
- Richard, A
- Tomaszewski, J
- Fragment-based Design
- SBDD
- Screening
- Structural Biology
- ADME/Tox Forum
- Program 2006
- Photo Gallery
- Hyderabad Conference
- Workshops & Training
- Program
- Exhibition
- Registration
- Jobs
- Contact
- Schedule
|
|
|
|
|
|
|
| About Joseph Tomaszewski (NCI) |
|
Dr. Joseph E. Tomaszewski, appointed as the Deputy Director of the Division of Cancer Treatment and Diagnosis in 2005, has been given responsibility for developing a new pharmacodynamic initiative within NCI to support Phase 0 clinical trials under the FDAs Exploratory-IND Guidance. As a result, new laboratories have been established to develop and validate PD assays in preclinical studies for use in the NCI’s Phase 0 studies at the NIH Clinical Center.
He has also been the Chief of the Toxicology and Pharmacology Branch (TPB), DTP, DCTD, NCI for the last 17 yrs. In this capacity, he has responsibility for the preclinical toxicological and pharmacological evaluation of all new cancer drugs that are developed by the NCI under a variety of government sponsored programs and more recently for the new NIDDK Type 1 Diabetes RAID and NIH RAID Pilot Programs. While at the NCI, he has been involved in the evaluation of between 160-180 diverse clinical candidates such as antimetabolites, topoisomerase inhibitors, antimetastatic agents, alkylating agents, angiogenesis inhibitors, tubulin inhibitors (Paclitaxel) and newer molecular targeted therapies such as Velcade (Proteasome Inhibitor), HDAcs, etc; and drugs to treat AIDS such as the reverse transcriptase inhibitors, Hivid and Videx and a variety of protease inhibitors.
In addition, his group also has responsibility for the evaluation of cancer biologicals such as monoclonal antibodies and immunotoxins (BL22) as well as vaccine and gene therapy products. More recently, his group has been involved in the evaluation of imaging agents for the NIH Clinical Center and the NCI under the DCIDE and JDC Programs. During this period, the TPB has moved away from development of NCEs using standard protocols to an agent-directed approach and recently he has developed a PK/PD abbreviated approach that is being implemented to support Phase 0 clinical trials in the NCI under the FDA’s Exploratory IND Guidance.
In order to facilitate the prediction of human sensitivity, he has fostered the development of in vitro assays such as a bone marrow assay that is highly predictive of human sensitivity and is used routinely in NCI drug development.
During his 20 yrs at the NCI, he and his group have supported the filing of more than 100 INDs/DMFs and 5 NDAs with the FDA. He is the author/coauthor of over 200 publications/ abstracts/ presentations at national and international meetings.
|
|
Predictive ADMET at the NCI
Joseph E. Tomaszewski, National Cancer Institute
The National Cancer Institute (NCI) typically relies on the development of in vitro and in vivo assays/studies to predict human sensitivity, PK parameters and toxicity rather than the development of computer modeling. The reasons for this approach include the inability to completely model animal systems in comparison to man. Several examples will be presented to illustrate this point.
In case study no. 1, the development of Epothilone D (Epo D) will be described, which is an example of large interspecies plasma stability and S9 Fraction metabolism differences that are not easily predicted. This is due in part to the fact that various species have different levels of esterase in their plasma and liver which would potentially inactivate Epo D, thereby preventing sufficient and sustainable plasma levels that are needed for activity in animal efficacy models. The objectives of the studies that were initially performed were to examine interspecies differences in esterase plasma stability and liver metabolism for Epo D in order to determine appropriate efficacy schedules and animal models for pharmacokinetic and toxicologic studies. The results from these studies indicated that the species differences was due: (1) to plasma instability of the drug in which the mouse is similar to the rat and much greater than that seen either in either the dog or man; (2) the metabolism of Epo D by esterases in the S-9 fraction of liver providing a similar profile with the mouse >> rat > dog > man. The results from these studies indicated that efficacy studies in the mouse must be performed by continuous intravenous infusion rather than bolus doses in order to achieve the appropriate exposure to produce tumor regressions in human tumor xenografts.
In example no. 2, studies with UCN-01, a staurosporin analog, in which plasma protein binding caused a serious under prediction of what happened in man, will be described. Efficacy/schedule studies and in vitro efficacy studies suggested that a 72-h continuous infusion would be appropriate to produce maximal activity. In rats and dogs, maximum tolerated doses produced plasma concentrations of approximately 0.2-0.3 microM. Initial protein binding studies indicated difference, but not as profound as seen in vivo. The in vivo results indicated that the: (1) pharmacokinetic half-life in man was greater than that observed in the dog , which was greater than the rat; (2) the MTD in Man was greater than the dog, which was greater than the rat. The primary reason for these differences was the high specific binding to human alpha-1 acid glycoprotein that was not observed in either the dog or the rat.
|
|
|
|
|
|
|
|
|
