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PRECLINICAL PHARMACOLOGY & TOXICOLOGY IN CANCER DRUG DEVELOPMENT

PRECLINICAL PHARMACOLOGY & TOXICOLOGY IN CANCER DRUG DEVELOPMENT. Joseph M. Covey, Ph.D. Toxicology & Pharmacology Branch DTP, DCTD, NCI. Preclinical Pharmacology & Toxicology: Why ?. Balance of : Regulatory Issues Need for information Science Practical Considerations

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PRECLINICAL PHARMACOLOGY & TOXICOLOGY IN CANCER DRUG DEVELOPMENT

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  1. PRECLINICAL PHARMACOLOGY & TOXICOLOGY IN CANCER DRUG DEVELOPMENT Joseph M. Covey, Ph.D. Toxicology & Pharmacology Branch DTP, DCTD, NCI

  2. Preclinical Pharmacology & Toxicology: Why? • Balance of: • Regulatory Issues • Need for information • Science • Practical Considerations • Preclinical Costs versus Patient Cost

  3. Reasons for Termination of Development of NCEs (Excluding Anti-Infectives) J. Ormerod (1994) Commercial Reasons Lack of Efficacy 5.0% 46.0% Lack of Efficacy 30.0% ADRs in Man Commercial Reasons 10.0% Misc 7.0% Misc 5.0% 7.0% ADRs in Man PK Animal Toxicity 16.0% 39.0% PK 11.0% Animal Toxicity 7.0% 17.0% Data taken from 7 UK-owned Companies (1964 - 1985)

  4. FDA Preclinical Pharmacology & Toxicology Requirements • DRUGS • Two Species - Rodent & Non-rodent • Clinical Route & Schedule • Pharmacokinetics - Optional • BIOLOGICALS • Most Relevant Species • Clinical Route & Schedule • Biodistribution

  5. Representative Surface Area to Weight Ratios (km) for Various Species(Freireich, et al, Cancer Chemotherapy Reports, 1966, 50: 219-244)

  6. T&PB Drug Evaluation Philosophy • Agent-Directed Studies • Pharmacologically (PK/PD) - Guided • Integrate With Preclinical Efficacy Data & the Proposed Clinical Protocol • Rational Evaluation of Role of Schedule Dependence, Pharmacodynamics, Pharmacokinetics & Metabolism in the Development of Toxicity • Relate Drug Levels and/or AUC (Plasma &/or Tissue), Biomarkers to Safety and to Occurrence & Severity of Toxicity • Extrapolate Toxic Effects Across Species

  7. Advantages Of Agent-DirectedDrug Development • Greater Scientific Basis for Development • Permits Greater Flexibility • Data Rich IND Submission to Support Phase I • Preclinical Potential ….. Less Expensive • Permits PK/PD-Guided Dose Escalation in Phase I • Optimal Schedule ….. Greater Chance of Success? • Patients ….. Greater Chance of Effective Therapy?

  8. Objectives Of Preclinical Pharmacology Studies For Anti-Neoplastic Drugs • Development of Sensitive Analytical Methods • Determine In Vitro Metabolism and Protein Binding • Analog Evaluation - Determine Optimal Development Candidate • Determine Pharmacokinetics in Various Species • Identification and Analysis of In Vivo Metabolites • Define Optimal Dose Schedule • Correlate CP and/or AUC with Efficacy, Safety & Toxicity and PD

  9. Key Pharmacology Contributions to Drug Development • 9-AC: Suspension 72 Hr civ • 17-AAG:Parent Efficacy Active metabolite Efficacy • Penclomedine: High CP MAX Neurotoxicity • CP < ThresholdNo Neurotoxicity • Isis 5320: High CP MAX BP, APTT, Bb • CP < ThresholdNo Toxic Effects • Halofuginone: Tissue AUC Efficacy (?) >> Plasma AUC

  10. Selective Retention of17-AAG in Tumors

  11. Objectives Of Preclinical Toxicology Studies For Anti-Neoplastic Drugs • DETERMINE IN APPROPRIATE ANIMAL MODELS: • The Maximum Tolerated Dose ( MTD ) • Dose Limiting Toxicities ( DLT ) • Schedule-Dependent Toxicity • Reversibility of Adverse Effects • A Safe Clinical Starting Dose

  12. Additional Agent-Directed Toxicology Study Requirements • Attain Efficacious Drug Levels in Plasma In Vivo • Correlate Drug Plasma Levels and/or AUC with Toxicity and Safety Across Species • Ameliorate Toxicity by Change in Route/Schedule • Compare Toxicity with Previously Studied Clinical Agents as Necessary

  13. 5'-CICGATCICG GCICTAGCIC-5' Interstrand G–G cross-link PYRROLOBENZODIAZEPINE (NSC 694501) Energy-minimized SJG-136 cross-linked DNA adduct View into minor groove View down axis

  14. Comet Assay 100 75 50 Percentage decrease in tail moment 25 0 0 75 25 50 100 HUMAN LYMPHOCYTES NSC 694501 Conc. (nM) PYRROLOBENZODIAZEPINE (NSC 694501):MEASUREMENT OF CROSSLINKING IN EX VIVO HUMAN LYMPHOCYTES USING COMET ASSAY Single Cell Gel Electrophoresis

  15. PYRROLOBENZODIAZEPINE (NSC 694501):Toxicity Concerns • Potent DNA Minor Groove Cross-Linking Alkylating Agent Similar to Bizelesin – Myelosuppression with Human Sensitivity Much Greater than Mouse • Anthramycin-Like Compound – Potential for Serious Cardiotoxicity

  16. BIZELESIN (NSC 615291):In Vitro Bone Marrow Toxicity Data 728X

  17. PYRROLOBENZODIAZEPINE(NSC 694501):In Vitro Bone Marrow Toxicity Data 3X

  18. PYRROLOBENZODIAZEPINE(NSC 694501):Projected Human Clinical MTD • IC90: Murine = 2640 pM, Human = 826 pM • MED: Murine = 240 g/m2 (TD, Dx5) • MTD: Murine = 1800 g/m2 (TD, Dx5) • MTD: Dog ~ 100 g/m2 (TD, Dx5) • Proj Hu MTD = Hu IC90/Ms IC90 x Ms MTD 0.31 x 1800 = 563 g/m2 (TD, Dx5)

  19. PYRROLOBENZODIAZEPINE (NSC-694501):MYELOSUPPRESSION • In Vitro: • Bizelesin: Human 728-fold > Mouse • Taxol: Human 5-fold > Mouse • PBD: Human 3-fold > Mouse Human CFU-GM IC90 826 pM Sensitive Tumor Lines GI50 170 - 1222 pM • In Vivo: • Dose Limiting in Rats & Dogs (+ GI) • Based on In Vitro Bone Marrow and In Vivo MTDs, Projected Human MTD for PBD is within Mouse Efficacy Range (MED and MTD) • PBD Has Greater Chance of Activity in Humans

  20. PYRROLOBENZODIAZEPINE (NSC-694501):Current Development Plans • Perform PK Studies at Effective Doses in Mouse • Determine if Effective Concentrations can be Achieved in Rat and Dog • Use Comet Assay for PK/PD Correlation in Mouse Lymphocytes & Tumor • Use Comet Assay for TK/PD Correlation in Rat and Dog Lymphocytes

  21. Approach to PK & Toxicology Studies Conclusions • Do Not Think of Tox as Simply Checking a Regulatory Box  • Develop Preclinical Plan For Each Agent Using All Available Data • In Vitro and In Vivo Preclinical Data Is Useful in Predicting Human Sensitivity and Toxicity

  22. Acknowledgements • T&PB Contractors • Pharmacology • Mayo Foundation • Ohio State University • Southern Research • Univ Alabama • Univ Pittsburgh • Univ Texas - MDA • Toxicology • Battelle • IIT Research Inst. • Southern Research • SRI International • Univ Illinois, Chicago • Pathology Assoc.

  23. T&PB Contact Information • Phone: 301-496-8777 • Fax: 301-480-4836 • E-mail: ncidtptpbinfo@mail.nih.gov • Web Address: http://dtp.nci.nih.gov/branches/tpb/index.html

  24. Our next speaker is: Dr. Edward Sausville Developmental Therapeutics Program for Dr. Louise Grochow, Cancer Therapy Evaluation Program

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