1
From Animal Scale-Up
to First-In-Human
Clinical Studies
{Chapters 32 & 33}
Jerry M. Collins, Ph.D.
Developmental Therapeutics Program
Division of Cancer Treatment and Diagnosis, NCI
Chapter 32
Section: Animal Scale-Up
Slides Supplied by:
Robert L. Dedrick, Ph.D.
Founder and Former Chief
Chemical Engineering Section, NIH
In a Chemical Plant, kilograms
of materials are made –
somehow linked to a test tube
process on a scale of milligrams
How do you get
from milligrams
to kilograms?
“SCALE-UP” How would “Scale-Up”
happen in BIOLOGY?
2
Many Biological Processes are Scaled by Body Weight
3
Allometric Chart
Convert Equations
to Log-Log Graph
Log-Log Graph
Physiologic-Based
Pharmacokinetics
“PB-PK”
Dedrick, RL, et al.
Biochem. Pharmacol, 1972
Compartmental Model for
Ara-C Pharmacokinetics
4
Core Principle of Physiologic-Based PK
Prediction, not Curve-Fitting
dose-normalized
concentrations in
4 mammalian species
(without metabolism)
Khor et al, Cancer Chemother Pharmacol, 1997
“Complex Dedrick Plot”
adjust x-axis for relative time
5
Rat Data
Scale-Up in vitro to in vivo:
cells culture to whole body
Human Data
Log-Log Graph
Ideas Borrowed from Bob Dedrick
Conversation between a Biologist and
an Engineering Consultant
[1] What are the similarities? (engineers)
[2] What are the differences? (biologists)
[3] How do you get from one set of facts
and circumstances to another?
● “Extrapolation”
● “Scale-Up”
6
//nihroadmap.nih.gov //nihroadmap.nih.gov
Cover: July 2011 issue
… This will speed the delivery of new drugs, diagnostics and medical devices to patients.
Note: NIAID, NHLBI, NCI, and other NIH units also have therapeutics-related programs
Not a new task for NCI:
Developmental Therapeutics Program Was Established by Congress in 1955
DTP.CANCER.GOV
NEXT.CANCER.GOV
Providing Services to Facilitate
Turning Discoveries into Medicines
7
First-In-Human (FIH)
Clinical Studies
<Chapter 33>
Phase 1 Clinical Studies
“First-in Human”
Jerry M. Collins, Ph.D. Developmental Therapeutics Program
Division of Cancer Treatment and Diagnosis, NCI
Re-Engineering Phase I (FIH) Trials
1. Pipeline/Funnel Pressure:
combinatorial/HTS, new Sponsors
2. To Phase I Faster, Less Preclinical Work
3. Fewer patients, homeopathic doses
4. More patients “near-Phase 2” doses
5. “Value-Added” factors
PK only: variability, metabolism/pharmacogenetics
PD: Decisions to Drop/Continue
8
Design of Phase 1 (FIH) Trial
Among all design features,
some choices remain essential
Starting Dose
Escalation Scheme
For Both Elements, Conflict Between
Caution/Safety vs. Efficiency/Efficacy
Pre-Defined
BIBLIOGRAPHY / COLLINS / PHASE 1
J.M.Collins, D.S.Zaharko, R.L.Dedrick, B.A.Chabner.
Potential roles for preclinical pharmacology in Phase I trials.
Cancer Treat. Rep. 70:73-80, 1986.
** Message: we do a lot of preclinical pharm studies;
- - what do we learn?
- - how is it used?
** Initial proposal for customized dose escalation.
J.M. Collins, C.K. Grieshaber, B.A. Chabner.
Pharmacologically-guided Phase I trials based upon
preclinical development.
J. Natl. Cancer Inst. 82:1321-1326, 1990.
** Note that title does not say “PK”
Intended as an overall platform
Summarizes mostly retrospectively
ADAPTIVE DESIGN
9
PK-PD Hypothesis:
When Comparing
Animal and Human Doses,
Expect Equal Toxicity for
Equal Drug Exposure
Concentration of Drug as
a Biomarker or Endpoint
Bridges Between Preclinical
and Clinical Development
Preclinical Clinical
Pharm/Tox Phase 1 Trials
--------------- -------------------
Mouse MTD Starting Dose
Blood Levels Blood Levels
Escalation Strategy
Acute Toxicity of Anticancer Drugs
Human versus Mouse
Dose Ratio AUC Ratio
10
Conclusion:
Hypothesis has merit.
Follow-Up:
What is underlying reason for
interspecies differences?
S.Markey, 8-Nov-01, <more general discussion, pp.169-170>
Additional Effects on Drug Metabolism
Species Differences
• Major differences in drug metabolism in different
species have been recognized for many years
both in gut microflora and CYP proteins
• Example: phenylbutazone half-life is:
3 h in rabbit
6 h in rat, guinea pig, dog
3 days in humans
Metabolism as the
Principal Confounding Factor
for First-in-Human Trials
11
major human metabolite
major rat metabolites
terfenadine/SELDANE®
fexofenadine/ALLEGRA®
parent versus metabolite
antihistaminic potency
about equimolar
cardiac ion channel potency
10,000-fold different
(parent is more toxic)
X
Pharmacodynamic Approach:
Target-Guided Dose Escalation
Preclinical Pharm/Tox Clinical Phase 1 Trials --------------------------------- ---------------------------------
Safety Factor
Reference Animal Dose Starting Human Dose
Stop or Escalate?
Define Target Goal Assess Target Impact
12
Guidance for Industry, Investigators, Reviewers
Exploratory IND Studies
FDA January 2006
Categories of Studies Include:
[1] Molecular Proof-of-Concept (pharmacologic concentrations)
[2] Functional Imaging
FDA’s Exploratory IND
enables NCI’s Phase Zero
“Historical” Phases of Human Evaluation
Phase 1: Safety, early signs of activity
Phase 2: Is activity promising?
Phase 3: Improve current therapy?
Phase 0: Mechanism of Action
Articulate and Answer the Key Question
Key question can be as simple as whether drug candidate is absorbed from GI tract
Readily Answered
Key Question for Phase Zero PARP Project:
Can DNA Repair Enzyme Be Inhibited?
(Need Tumor Sample and Suitable Assay!)
13
0
0.2
0.4
0.6
0.8
1
1.2
0 4 8 12 16 20 24
Time (hours)
Pla
sm
a C
on
ce
ntr
ati
on
(u
M)
10 mg (N = 3)
25 mg (N = 3)
50 mg (N = 7)
0.21 µM target
Veliparib Phase Zero Plasma PK
Target Concentration
S.Kummar, ASCO 2007
First NCI Phase Zero Project
PARP enzyme inhibitor
Goals
Can Target Plasma Concentration Be Achieved Orally?
Outcomes
YES
Can Tumor Biopsy Provide Definitive
Results?
PAR Inhibition in Tumor Biopsies 3-6 Hours Post Dose
0
20
40
60
80
100
120
Pe
rce
nt
of
Ba
se
lin
e
Baseline Post-Dose
Pt 4
Pt 5
Pt 6
Pt 7
Pt 10
Pt 11
S.Kummar, T.A.T. 2008
14
First NCI Phase Zero Project
PARP enzyme inhibitor
Goals
Can Target Plasma Concentration Be Achieved Orally? - - - - - - - - - - - - - - - - - -
Can Tumor Biopsy Provide Definitive
Results?
Outcomes
YES
YES
PK
PD
Inhibition by dose and time
Functional Imaging via PET:
Biomarkers for Treatment Evaluation
Does treatment impact the desired target?
What is the minimum/maximum dose?
How to select interval between courses?
CONTEXT:
Individual Patient, or New Agent Development
MAO-B
Inhibition by
Lazabamide
J.Fowler,BNL
Neurology(93)
15
First-In-Human Trials
Identity Crisis?
What is Inherent in
First-In-Human Trials?
<surprise!>
FDA
NIH
Pittsburgh
Indianapolis NIA/NIDA/Baltimore
Dartmouth
U
C
L
A
DUKE University