# Presentation: 179432

## PRECLINICAL PHARMACOLOGY & TOXICOLOGY OF ANTI-NEOPLASTIC AGENTSTHE NCI PERSPECTIVE

**Joseph E. Tomaszewski, Ph.D.**
**Toxicology & Pharmacology Branch**
**DTP, DCTD, NCI**

## 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

**Lack of Efficacy**

**46.0%**

**Commercial**
**   ****Reasons**

**7.0%**

**ADRs in Man**

**16.0%**

**PK**

**7.0%**

**Animal Toxicity**

**17.0%**

**Misc**

**7.0%**

**Lack of Efficacy**

**30.0%**

**Commercial Reasons**

**5.0%**

**ADRs in Man**

**10.0%**

**PK**

**39.0%**

**Animal Toxicity**

**11.0%**

**Misc**

**5.0%**

**J. Ormerod  (1994)**

**Data taken from 7 UK-owned **

**Companies  (1964 - 1985)**

## 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.**_** ...”**

## 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**

## REPRESENTATIVE SURFACE AREA TO WEIGHT RATIOS (km) FOR VARIOUS SPECIES 1    ((Freireich, et al, Cancer Chemother Repts, 1966, 50, 219-244)) 

## NCI STANDARDIZED PRECLINICAL TOXICOLOGY PROTOCOLS FOR ANTI-NEOPLASTIC AGENTS   (1980 - 1988)

_**Mouse**_** **_**Lethality**_** Studies **
_**Dog**_** **_**Toxicity**_** Studies**
_**Rodent**_** (Rat) **_**Toxicity**_** Studies**

**Determine LD****10**** on Dx1 & Dx5 Schedules**
**Assess safety of 1/10 LD****10****  Determine DLTs on Dx1 & Dx5 Schedules.**
**Assess safety of 1/10 LD****10****  Determine DLTs on Dx1 & Dx5 Schedules.**

## 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 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?**

## 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 C****P**** and/or AUC with Efficacy, Safety & Toxicity**
**Analog Evaluation - Determine Optimal Development Candidate**

## KEY PHARMACOLOGY CONTRIBUTIONS TO DRUG DEVELOPMENT

**9-AC:****	****Suspension****	****	****	****72 Hr *****civ***
**Dolastatin 10:***** ******	*****High C****P MAX****	****	****	****Efficacy**
**Penclomedine:****	****High C****P MAX****	****	****	****Neurotoxicity**
**	****	****C****P**** < ****Threshold****	****	****	**_**No**_** Neurotoxicity**
**Isis 5320:****	****High C****P MAX**** ****	****	****	****BP********, APTT********, Bb******
***	******	****** *****C****P**** < ****Threshold**** ****	****	****	**_**No**_** Toxic Effects**
**8-Cl-c-AMP:****	*****civ*****	****	****	****	**** ******** Cl****TB****, ******** C****P SS**

- KEY _PHARMACOLOGY_ CONTRIBUTIONS TO DRUG DEVELOPMENT

## 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

**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**

## 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**
**O****6**** –Benzylguanine:****	****Bolus****	****	****	****CNS, HR ******
***	******	*****Infusion****	****	****	****Neutrophilia*****	***

## DEVELOPMENT EXAMPLE:9-AMINO-20[S]CAMPTOTHECIN (NSC-603071)

**[ Topoisomerase I Inhibitor ]**

## 9-AMINO-20[S]CAMPTOTHECIN  (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:****	****C****P Max****  11.8 ****μM,   *****t *****1⁄2  1.38 hr**
***sc*****, Solution:****	****C****P Max****  1.95 ****μM,   *****t *****1⁄2  1.58 hr**
***sc*****, Suspension:****	****C****P Max****  0.25 ****μM,   *****t *****1⁄2  17.5 hr****	**

## 9-AMINO-20[S]CAMPTOTHECIN  (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 CFU****GM**

## 9-AMINO-20[S]CAMPTOTHECIN  (NSC-603071):     IN VITRO BONE MARROW DATA

****

- 

****

****

- 

****

****

****

****

****

****

****

****

****

****

****

****

****

****

****

**0.01**

**0.1**

**1**

**10**

**100**

**1000**

**DRUG CONCENTRATION  (nM)**

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**CFU-GM - % INHIBITION**

**CANINE**

**HUMAN**

**MURINE**

****

** ******

- 

## 9-AMINO[20S]CAMPTOTHECIN  (NSC 603071):  IN VITRO & IN VIVO TOXICITY DATA

## 9-AMINO[20S]CAMPTOTHECIN (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.**

## 9-AMINO-20[S]CAMPTOTHECIN  (NSC-603071):CORRELATION OF EFFICACY WITH TOXICITY & PHARMACOKINETICS

## ACKNOWLEDGEMENTS

_**T&PB 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.**

## ACKNOWLEDGEMENTS

_**T&PB 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**

## T&P CONTACT INFORMATION

**Phone No:****	****301-496-8777**
**Fax No:****	****301-480-4836**
**E-mail:****	****	**_[ncidtptpbinfo@](mailto:ncidtptpbinfo@)__[mail.nih.gov](http://dtp.nci.nih.gov/branches/tpb/index.html)_
**Web Address: **_[http://dtp.nci.nih.gov/branches/tpb/index.html](mailto:tpb@fcrdc.nci.nih.gov)_

## Thank you,

**Are there any Questions?**

## Our next speaker is:

**Dr. Louise Grochow**
**Investigational Drug Branch**
**Cancer Therapy Evaluation Program**

## Slide 27

## Slide 28

## 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**