PRECLINICAL PHARMACOLOGY

1
PRECLINICAL PHARMACOLOGY TOXICOLOGY OF
ANTI-NEOPLASTIC AGENTS????THE NCI PERSPECTIVE

• Joseph E. Tomaszewski, 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
REGULATORY CONSIDERATIONS FOR PRE-CLINICAL
DEVELOPMENT OF ANTICANCER DRUGS DeGeorge, et
al, CCP (1998) 41 173-185
The types of preclinical studies expected for
support of clinical trials and marketing of a new
drug depends on both the intended use of the drug
and the population of patients being studied and
treated. In situations where potential benefits
are greatest (Advanced, life-threatening
disease), greater risks of treatment toxicity can
be accepted and the required preclinical testing
can be minimal.
5
FDA PRECLINICAL PHARMACOLOGY TOXICOLOGY
REQUIREMENTS

• DRUGS
• Two Species - Rodent Non-rodent
• Clinical Route Schedule
• Follow NCI Guidelines
• Pharmacokinetics - Optional

• BIOLOGICALS
• Most Relevant Species
• Clinical Route Schedule

6
REPRESENTATIVE SURFACE AREA TO WEIGHT RATIOS (km)
FOR VARIOUS SPECIES 1 ((Freireich, et al,
Cancer Chemother Repts, 1966, 50, 219-244))
7
NCI STANDARDIZED PRECLINICAL TOXICOLOGY PROTOCOLS
FOR ANTI-NEOPLASTIC AGENTS (1980 - 1988)

• Determine LD10 on Dx1 Dx5 Schedules
• Assess safety of 1/10 LD10 Determine DLTs on Dx1
  Dx5 Schedules.
• Assess safety of 1/10 LD10 Determine DLTs on Dx1
  Dx5 Schedules.

• Mouse Lethality Studies
• Dog Toxicity Studies
• Rodent (Rat) Toxicity Studies

8
TPB 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

9
AGENT-DIRECTED versus STANDARD PROTOCOL 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?

10
OBJECTIVES OF PRECLINICAL PHARMACOLOGY STUDIES
FOR ANTI-NEOPLASTIC DRUGS

• Development of Sensitive Analytical Methods for
  Drugs in Biological Fluids Tissues
• Determine In Vitro Stability and Protein Binding
• Determine Pharmacokinetics in Various Species
• Identification and Analysis of Metabolites
• Define Optimal Dose Schedule and Blood Sampling
  Times
• Define CP and/or AUC with Efficacy, Safety
  Toxicity
• Analog Evaluation - Determine Optimal Development
  Candidate

11
KEY PHARMACOLOGY CONTRIBUTIONS TO DRUG DEVELOPMENT

• 9-AC Suspension 72 Hr civ
• Dolastatin 10 High CP MAX Efficacy
• Penclomedine High CP MAX Neurotoxicity
• CP lt Threshold No Neurotoxicity
• Isis 5320 High CP MAX BP?, APTT?, Bb?
• CP lt Threshold No Toxic Effects
• 8-Cl-c-AMP civ ? ClTB, ? CP SS

12
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

13
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

14
SCHEDULE and ROUTE versus TOXICITY

• Pyrazoloacridine Bolus iv Neurotoxicity
• 1 Hr civ Bone Marrow
• Penclomedine Bolus iv Neurotoxicity
• 1 Hr Dx5 BM ( Neuro)
• 5 Hr civ Neuro Death
• Oral BM
• O6 Benzylguanine Bolus CNS, HR ?
• Infusion Neutrophilia

15
DEVELOPMENT EXAMPLE9-AMINO-20SCAMPTOTHECIN
(NSC-603071)
Topoisomerase I Inhibitor
16
9-AMINO-20SCAMPTOTHECIN (NSC-603071)
PRECLINICAL EFFICACY PK RESULTS

• EFFICACY
• Best Rx sc, suspension, q4Dx8
• Good Rx sc, solution, Dx32
• None Rx sc, solution, q4Dx8

• PHARMACOKINETICS
• iv, Solution CP Max 11.8 µM, t ½ 1.38 hr
• sc, Solution CP Max 1.95 µM, t ½ 1.58 hr
• sc, Suspension CP Max 0.25 µM, t ½ 17.5 hr

17
9-AMINO-20SCAMPTOTHECIN (NSC-603071)
PRECLINICAL PK TOXICOLOGY STUDIES

• Mice Pharmacokinetics - iv and sc
• Repeated (q4Dx3) sc Dose Toxicity Study
• Rats Pharmacokinetics - Bolus iv
• 72 Hr civ IND-Directed Toxicity Study
• Dogs PK/Dose RF Study - Bolus iv
• 48 Hr civ Dose RF Toxicity Study
• 72 Hr civ Dose RF Toxicity Study
• 72 Hr civ IND-Directed Toxicity Study
• In Vitro Murine, Canine, Human CFUGM

18
9-AMINO-20SCAMPTOTHECIN (NSC-603071) IN
VITRO BONE MARROW DATA
120
?
CANINE
?
HUMAN
'
?
?
?
?
?
?
100
?
?
MURINE
?
?
?
80
?
CFU-GM - INHIBITION
?
60
?
?
40
?
?
?
20
?
?
0
0.01
0.1
1
10
100
1000
DRUG CONCENTRATION (nM)
19
9-AMINO20SCAMPTOTHECIN (NSC 603071) IN
VITRO IN VIVO TOXICITY DATA
20
9-AMINO20SCAMPTOTHECIN (NSC 603071)
DEVELOPMENT CONCLUSIONS

• Bone Marrow and GI Toxicity are Dose Limiting in
  Mice, Rats and Dogs and Should be in Man.
• Dogs are the Most Sensitive Species.
• In Vitro Bone Marrow Data Predicts that Man will
  be as Sensitive as the Dog.
• The MTD in Man Dog Should be Comparable.
• 9-AC Lactone Plasma Levels and AUC Required for
  Efficacy in the Mouse are Not Achievable in the
  Dog.

• Thus, 9-AC Should not be Effective in Man.

21
9-AMINO-20SCAMPTOTHECIN (NSC-603071)CORRELATI
ON OF EFFICACY WITH TOXICITY PHARMACOKINETICS
22
ACKNOWLEDGEMENTS

• TPB Contractors
• Pharmacology
• Mayo Foundation
• Ohio State University
• Southern Research
• Univ Alabama
• Univ Pittsburgh
• Univ Texas - MDA

• Toxicology
• Battelle Memorial
• IITRI
• Southern Research
• SRI International
• Univ Illinois, Chicago
• Pathology Assoc.

23
ACKNOWLEDGEMENTS

• TPB Staff
• PK Joseph M. Covey, Ph.D.
• PK Julie K Rhie, R.Ph., Ph.D.
• Tox Susan J. Donohue, Ph.D.
• Tox Elizabeth R. Glaze, Ph.D.
• Tox Karen M. Schweikart, Ph.D.
• Tox Adaline C. Smith, Ph.D., DABT
• Sec Victoria Cordelli

24
TP CONTACT INFORMATION

• Phone No 301-496-8777
• Fax No 301-480-4836
• E-mail ncidtptpbinfo_at_mail.nih.gov
• Web Address http//dtp.nci.nih.gov/branches/tpb/i
  ndex.html

25
Thank you,

• Are there any Questions?

26
Our next speaker is Dr. Louise
Grochow Investigational Drug Branch Cancer
Therapy Evaluation Program
27
(No Transcript)
28
(No Transcript)
29
EORTC MINIMUM REQUIREMENTS FOR THE TOXICOLOGY OF
A NEW CYTOSTATIC AGENT FOR PHASE I TRIALS

• 
  1987 1995
• Dx1 ip Mouse Lethality Study x NA
• Dx1 iv Mouse Lethality Study x x
• Dx1 Toxicity Study in Mice x NA
• Detailed Toxicity in Mice (Clin Prot) NA
  x
• Multiple Dose ip Toxicity Study in Mice x
  NA
• Toxicity Check in Rats at Clinical Dose x
  NA
• Toxicity Study in Rats (Clin Prot) NA
  x
• Limited PK Study in Mice (AUC at MTD) NA
  x