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PRECLINICAL PHARMACOLOGY & TOXICOLOGY IN CANCER DRUG DEVELOPMENT. Adaline C. Smith, Ph.D., D.A.B.T. 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

PRECLINICAL PHARMACOLOGY & TOXICOLOGY IN CANCER DRUG DEVELOPMENT

Adaline C. Smith, Ph.D., D.A.B.T.

Toxicology & Pharmacology Branch

DTP, DCTD, NCI

preclinical pharmacology toxicology why
PRECLINICAL PHARMACOLOGY & TOXICOLOGY: WHY?
  • Balance of:
    • Regulatory Issues
    • Need for information
    • Science
    • Practical Considerations
    • Preclinical Costs versus Patient Cost
reasons for termination of development of nces
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)

fda preclinical pharmacology toxicology requirements
FDA PRECLINICAL PHARMACOLOGY & TOXICOLOGY REQUIREMENTS
  • DRUGS
    • Two Species - Rodent & Non-rodent
    • Clinical Route & Schedule
    • Pharmacokinetics - Optional
  • BIOLOGICALS
    • Most Relevant Species
    • Clinical Route & Schedule
slide5

REPRESENTATIVE SURFACE AREA TO WEIGHT RATIOS (km) FOR VARIOUS SPECIES(Freireich, et al, Cancer Chemotherapy Reports, 1966, 50: 219-244)

t pb drug evaluation philosophy
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
agent directed drug development
AGENT-DIRECTED DRUG 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?
objectives of preclinical pharmacology studies for anti neoplastic drugs
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
key pharmacology contributions to drug development
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

objectives of preclinical toxicology studies for anti neoplastic drugs
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
additional agent directed toxicology study requirements
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 Accepted Clinical Agents as Necessary
pyrrolobenzodiazepine nsc 694501

5'-CICGATCICG

GCICTAGCIC-5'

Interstrand G–G cross-link

PYRROLOBENZODIAZEPINE (NSC-694501)

Energy-minimised SJG-136 cross-linked DNA adduct

view into minor groove

view down axis

slide13

100

75

50

25

0

0

25

50

75

100

PYRROLOBENZODIAZEPINE (NSC-694501):MEASUREMENT OF CROSSLINKING IN EX VIVO HUMAN LYMPHOCYTES USING COMET ASSAY

Comet Assay

Percentage decrease in tail moment

HUMAN LYMPHOCYTES

NSC 694501 Conc. (nM)

pyrrolobenzodiazepine nsc 694501 toxicity concerns
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
pyrrolobenzodiazepine nsc 694501 projected human clinical mtd
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 ~ 200 g/m2 (TD, Dx5)
  • Proj Hu MTD = Hu IC90/MS IC90 x Ms MTD

0.31 x 1800 = 563 g/m2 (TD, Dx5)

pyrrolobenzodiazepine nsc 694501 myelosuppression
PYRROLOBENZODIAZEPINE (NSC-694501):MYELOSUPPRESSION
  • In Vitro:
      • Bizelesin: Human 728-fold > Mouse
      • Taxol: Human 5-fold > Mouse
      • PBD: Human 3-fold > Mouse (IC90 826 nM)
      • HTCFA: PBD IC90 20-30 nM
  • 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
pyrrolobenzodiazepine nsc 694501 current development plans
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 Lymph & Tumor
  • Use Comet Assay for TK/PD Correlation in Rat and Dog Lymph
approach to toxicology studies conclusions
APPROACH TO 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
acknowledgements
ACKNOWLEDGEMENTS
  • T&PB Contractors
    • Pharmacology
      • Mayo Foundation
      • Ohio State University
      • Southern Research
      • Univ Alabama
      • Univ Pittsburgh
      • Univ Texas - MDA
  • Toxicology
    • Battelle
    • IIT Research
    • Southern Research
    • SRI International
    • Univ Illinois, Chicago
    • Pathology Assoc.
t p contact information
T&P CONTACT INFORMATION
  • Phone No: 301-496-8777
  • Fax No: 301-480-4836
  • E-mail: tpb@dtax2.ncifcrf.gov
  • Web Address: http://dtp.nci.nih.gov/branches/tpb/index.html
slide23

Our next speaker is:

Dr. Edward Sausville

Developmental Therapeutics Program

for Dr. Louise Grochow,

Cancer Therapy Evaluation Program