Principles of

Clinical Pharmacology
 Introduction to
Pharmacology, Drug
Development and
Clinical Pharmacology

Dr. William Douglas Figg, Sr, PharmD, MBA

Deputy Chief, Genitourinary Malignancies Branch
Head, Molecular Pharmacology Section
National Cancer Institute
National Institutes of Health
 Introduction to Pharmacology, Drug
Development and Clinical Pharmacology

W. Douglas Figg, Pharm.D.

Center for Cancer Research
National Cancer Institute
National Institutes of Health,
Bethesda, MD USA
 Definition of Pharmacology
Pharmacology is the branch of biology concerned
with the study of drug action, where a drug can be
broadly defined as any man-made, natural, or
endogenous molecule which exerts a biochemical or
physiological effect on the cell, tissue, organ, or
organism
 Definition of Clinical Pharmacology
Clinical pharmacology is the science of drugs and
their clinical use. It is underpinned by the basic
science of pharmacology, with an added focus on the
application of pharmacological principles.
The Need for Clinical Pharmacologist

48.9% of American take at least one Rx Drug

23.1% take three or more Rx Drugs
11.9% take five or more Rx Drugs
75.2% of visits to physician involve drug therapy
4 billion Rx filled in retail pharmacies per year
$734,100,000,000 – Global Annual
Prescription Pharmaceutical Sales for
2015

Approx. half of the sales are in the US

Twelve products had annual sales of

over $5 bn/yr
Drug Development
 Cost of Developing Drugs
• $802 Million (estimate)
– Includes the cost of drugs that failed
– Clinical development accounts for 72% of that
– Some estimate $2 bn

• Median time from synthesis to FDA approval -

16.2 yrs for anticancer agents
- 4.4 yr preclin,
- 10.4 yr clinical,
- 1.4 yr FDA evaluation

• 13.7 yrs median time for development of

cardiovascular agent
Cancer drugs have the lowest overall rate of success, with just
5.1% of drugs that enter Phase 1 trials ultimately reaching FDA
approval. The highest success rate, of 26.1%, is seen in blood-
related conditions like hemophilia, anemia and blood protein
deficiencies.

Excluding cancer drugs (which made up 31% of the drug

programs studied) will increase the overall success rates of all
other drugs to 11.9%.

Phase 2 trials are where most drugs fail. Only 31% of drugs that
enter Phase 2 studies go on to Phase 3, either due to failure of
the study or lack of funding.
85% of drugs that are submitted to the FDA receive approval

Drugs for rare diseases are far more likely to succeed, with
25% of rare disease drugs that enter clinical trials getting FDA
approval. The lowest rates of success are seen in chronic
diseases with large patient populations, which have an average
success rate of 8.7%.

58% of drugs that begin Phase 3 trials are later submitted to the
FDA for approval.
Objectives of Phase I Trials
• Determine MTD for Phase II Dose

• Characterize SE/DLT

• Pharmacokinetics/Pharmacodynamics

• What is the starting dose and

escalation?
For most therapeutic classes
(cardiovascular, infectious disease,
etc.) Phase I studies are done in
Normal Volunteers

Phase I trials in Oncology are

routinely done in patients with
cancer
 Phase II Trial
• Determine the Efficacy in Different
Tumor Types
• Refine the Pharmacokinetic Data
• Single Arm - typically
• Single Institution - typically
• Maximize the chance of Detecting
Clinical Response or Biological
Activity
 Phase II Trial
• Two-Stage Design
– Looking for 1 in 12-15 pts, then expand
to 30-40 pts

• 0 in 12 - There is only a 10% chance

of rejecting a drug that has a true
response rate of 20%
No standard formula for Making
Phase III “go/no go” Decisions
 Phase III
• Large (hundreds of patients)
• Randomized
• Multiinstitutional
• Response Intensive
• Control group usually receives
standard of care plus placebo
• Broad Selection of Pts to Represent
Community
 Endpoints for the FDA
• TTP/PFS

• Overall Survival

• Relief of Symptoms

• Delay of Event
 Orphan Drug Status
• Drugs intended to treat disease affecting
fewer than 200,000 people in US
– Affects >200,000 persons in U.S. but no reasonable
expectation that cost of development will be
recovered from U.S. sales

• Allows longer period of market exclusivity

 Types of Approval
• Regular approval
– Direct evidence of clinical benefit (e.g.,
improved survival or reduction in
symptoms)
– Improvement in establish surrogate for
clinical benefit (e.g., durable CR’s in acute
leukemia)
• Accelerated approval
– Surrogate endpoint reasonably likely to
predict clinical benefit (e.g., ORR)

21
 Accelerated Approval
• FDA Intent
– to make drugs available quicker for life
threatening disease

– Approval based of preliminary evidence,

such as surrogate marker, prior to
formal demonstration of patient benefit
 Phase IV Trials
• Post-marketing period
• Pharma uses to expand market indication
• Required for Drugs that Receive
Accelerated approval by FDA
• Median Duration - 53.9 mo
 Translating Clinical Trial Results into
Clinical Care of Oncology Patients

• Tannock and colleagues – compared the overall survival of

docetaxel plus prednisone (q 3 wks)
within their institution 314 routine practice treat w D/P
43 enrolled on trials tx w D/P
• Result: OS = 13.6 months (routine) vs 20.4 months (trial)
• TAX327 Results: OS = 19.2 months (published trial)

If they limited their “routine patients” to eligibility criteria of trial:

OS = 16.7 months
 Success Rate
• Clinical approval success rate for all anticancer
agents 13.4% (1993-2004)
- Small Molecules 14.3%
- Large Molecules 11.5%
• Agents developed for hematologic indications had
a higher clinical approval success rate (36% vs
9.8%)
• Success of second and third indication was
dependent on approval of the first indication
– (only 2.5% and 1.8% if first indication failed)
DiMasi et al. Tufts Center for Study of Drug Development
Four Main Reasons a Drug Fail
• Lack of Efficacy
• Side Effects
• Pharmacogenetics
• Pharmacokinetics
– Bioavailability
– Half-life
– Protein Binding
– Drug Interactions
 asdf
Three Principles of Pharmacology established…
 16th Century
asdf
Three Principles of Pharmacology established…

-Each disease has a specific cause for which there is

a specific remedy

-Each natural remedy (usually a material of plant

origin) has an identifiable component which is
responsible for its efficacy

-The size of the dose determines the degree of the

response
 Paracelsus
• Phillipus Aureolus Theophrastus Bombastus von Hohenheim, 1493-1541,
late Middle Ages was a Swiss physician
• Father of Toxicology
• Credited with “the dose makes the poison”
-Concept that distinguishes pharmacology
from toxicology
-Basis of the dose-response relationship
-Remedy versus poison
• Focused on the “toxicon” as the primary toxic agent
 Drug Actions
Pharmacology and Toxicology differ?

• Pharmacology is the interaction of chemicals or

macromolecules with biological systems to yield
therapeutic or other beneficial effect

• Toxicology is a field of science that helps us

understand the harmful effects that chemicals,
substances, or situations, can have on people,
animals, and the environment.
 Definition of Side Effect
In medicine, a side effect is an effect, whether
therapeutic or adverse, that is secondary to the one
intended; although the term is predominantly
employed to describe adverse effects, it can also
apply to beneficial, but unintended, consequences of
the use of a drug.
 Definition of Side Effect
In medicine, a side effect is an effect, whether
therapeutic or adverse, that is secondary to the one
intended; although the term is predominantly
employed to describe adverse effects, it can also
apply to beneficial, but unintended, consequences of
the use of a drug.

Sildenafil was synthesized by Pfizer and was initially

studied for use in hypertension and angina
pectoris. Phase I trial suggested the drug had little
effect on angina, but it could induce marked penile
erection.
Common Terminology Criteria for Adverse
Events (CTCAE)
• An adverse event (AE) is any unfavorable and
unintended (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use
of medical treatment or procedure that may or may not
be considered related to the medical treatment or
procedure
• Grade refers to the severity of the AE
• Grade 1 Mild AE
• Grade 2 Moderate AE
• Grade 3 Severe AE
• Grade 4 Life-threatening or disabling AE
• Grade 5 Death related to the AE
Examples of Quantitative Assessments
Examples of Qualitative Assessments
Narrow Therapeutic Window for most Anticancer Agents

Increased risk of
toxicity
Plasma Concentration

Minimum effective
concentration

Time
Drug Exposure-Effect Relationship

I
Absorption
N Tissue Effect:
Dose Distribution
P Toxicity, Efficacy
Metabolism
U Biological Effect
Elimination
T

Pharmacokinetics (PK) Pharmacodynamics (PD)

(Drug Disposition) (Drug Effects)
Drug Exposure-Effect Relationship

I
Absorption
N Tissue Effect:
Dose Distribution
P Toxicity, Efficacy
Metabolism
U Biological Effect
Elimination
T

Pharmacokinetics (PK) Pharmacodynamics (PD)

(Drug Disposition) (Drug Effects)

Genetic variation
Pharmacodynamics
 Most Drugs work via Receptor
“Drug receptor or drug target” is a cellular
macromolecule or macromolecular complex with
which the drug interacts to elicit a cellular
response

Drugs commonly alter the rate or magnitude of

an intrinsic cellular response rather than create
new responses
 Drug-Receptor Binding
• Occupancy Theory: The response of a tissue to
a drug (exogenous) or ligand (endogenous or
exogenous) is a function of the number of
receptors bound (or “occupied”) to the drug
– Site on receptor where a drug binds is the binding site
– The concentration of the drug/ligand is an important
factor for the extent of receptor binding
– Typically need to reach a threshold of receptor
occupancy by drug/ligand to see the effect in the
tissue (cumulative nature of the response)
 Agonists
• Drugs that bind to physiological receptors
and mimic the regulatory effects of the
endogenous signaling compounds
– Primary agonist is a drug that binds to the same
recognition site on the receptor (called the
orthosteric binding site) as the endogenous ligand
– Allosteric agonist is a drug that binds to a different
region on the receptor (called the allosteric or
allotopic binding site) as the endogenous ligand
• Allosteric agonist will still mimic the effects of
primary agonists
 Antagonists
• Drugs that block or reduce the action
of an agonist
– Competitive: competes with an agonist for
the same or overlapping site on the receptor
– Noncompetitive: interacts with other sites on
the receptor (allosteric antagonism)
– Functional: indirectly inhibit the cellular or
physiological effects of the agonist
AFFIRM – Enzalutamide (Post-Chemo)

Scher HI, et. al. NEJM 2013;367(13):1187-1188

 Partial Agonist
• Cannot produce the maximal
response of which the tissue is
capable, even when it binds to the
same number of receptors
 Drug Properties
• Specific binding of drug to receptor depends on
the physical and chemical properties of the drug
• Important factors include hydrophobicity,
ionization state (pKa), conformation, and
stereochemistry
• Warfarin exists as a racemic mixture of S and R
enantiomers
• S is four times more potent than R because it has stronger
interactions to the binding site of Vitamin K epoxide
reductase
• Other examples include the anti-arythmic drug
sotalol and the anti-hypertensive drug labetalol
Thalidomide Prevents Limb Development

Appox 10,000 birth

defect (phocomelia)
late 1950/early 1960’s
primarily in Europe,
Canada and Australia
from a single
exposure
of thalidomide to
the fetus

Highest risk of
teratogenicity when
drug was taken
between week 3 to 8
weeks
 Receptor Properties
• Contain hydrophobic (often inside protein or
lipid bilayer) and hydrophilic (protein exterior
surface) segments of their protein
• Binding sites possess unique chemical
properties based on
unique folding of the
protein
 Drug-Receptor Bonds

Often a combination of interactions are responsible for drug-receptor binding. It is the

sum total of relatively weak interactions that create a strong interaction (high affinity)
between the drug and its receptor.
 Example
Imatinib Interaction with the BCR-Abl Kinase
Sorafenib
Serine/threonine Kinases Receptor Tyrosine Kinases
Kinase IC50 (nM) Kinase IC50 (nM)
Raf-1 6 VEGFR-1 26
B-Raf 25 VEGFR-2 90
B-raf V600E 38 VEGFR-3* 20
P38 38 FLT3 33
Mnk-2 150 RET# 47
ERK-1, MEK- 1, PDGFR-b* 57
PKA, PKB, PKC, C-KIT 68
cdk1/cyclinB, >10,000
pim-1 FGFR-1 580
c-met, IGFR-1, EGFR,
HER2, LCK >10,000
 Small Molecule Inhibitors of VEGFR

Inhibitor VEGFR1 VEGFR2 VEGFR3 PDGFR cKIT EGFR Other

Sunitinib + + - + + - FGFR

Vatalanib + + + + + - cFms

Vandetanib - + + +/- - + ret

Cediranib + ++ + + - -

Pazopanib + + + -

Sorafenib - + + + + - Raf

Axitinib + + + + + -

XL-184 + + + + Met

AMG-706 + + + +

BIBF1120 + + + + FGFR
Positive Randomized Phase III Trials of TKIs

Drug Setting Reference

Sunitinib Renal cell Motzer RJ, et al. N Engl J Med.
carcinoma; 2007;356:115-124.
imatinib-
resistant GIST

Sorafenib Renal cell Escudier B, et al. J Clin Oncol.

carcinoma 2009;27:3312-3318.
Escudier B, et al. N Engl J Med.
2007;356:125-134.

Sorafenib Hepatocellular Llovet JM, et al. N Engl J Med

carcinoma 2008;359:378-390.
Cheng AL, et al. Lancet Oncol.
2009;10:25-34.

Pazopanib Renal cell Sternberg CN, et al. J Clin Oncol.

carcinoma 2010;28:1061-1068.
 Drug-Receptor Interactionasdf
The response of drug binding to receptor is influenced by…
Adrenergic Receptor Selectivity
asdf
 Induced Fit Bindingasdf

• Binding of a drug to its receptor results in a conformational

change in the receptor that enhances the affinity of the drug
for the receptor
-This goes beyond the old (static) idea of a “lock and
key” model of drug-receptor binding
• Change in shape induced by drug is often identical to that
caused by the ligand
-Insulin analogues (exogenous) stimulate insulin
receptor to the same extent as insulin (endogenous)
despite slight differences in amino acid sequences
Formation of Platinum-DNA Adducts
Inhibition of Uptake with Ursolic Acid in
OATP1B3 Expressing CHO Cells
Testosterone Dihydrotestosterone Androstenedione

Ki is the inhibition
dissociation
constant in Chinese
hamster ovary cells
Androstenedione

Dihydrotestosterone

Testosterone
Sissung et al. Mol Cancer Res 2017
 Rationale Drug Design
• Application of “structure-activity” relationships
to develop new drugs with improved
pharmacological activity
• 1st begun by Josef von Merig (student of
Schmiedeberge) and Emil Fisher (organic
chemist)
• Alter structure of hypnotic drugs
(transquilizers) to increase how well they work
• First true chemical “designed” was diethyl
barbituric acid or Barbital
– Patented and marketed by Bayer
– Used as a sleeping aid from 1903-1950s
Mechanism of Action of Thalidomide

Franks et al (Figg) Lancet 2004

Thalidomide Analogs Activity in the
Zebra Fish Angiogenesis Model

Number

•Each symbol represents a

different analog (n=89)
Thalidomide Analogs Anti-inflammatory Activity
 >315 novel thalidomide analogs

Establish HUVEC
RAW Establish
anti- Z fish
246.7
anti-
angiogenic Fish inflammatory
activity RAR tail
activity

16 anti-angiogenic 10 anti-inflammatory
3 both

Xenografts
NCI60

LEADS
Ongoing project: SAR of thalidomide analogs

•Molecular activity
maps show where in
the molecule specific
structural changes
affect activity or
potency measured in
our bioassays

•Detection of
loss/increase of activity

•Detection of arge
changes
in potency

Beedie (Figg) Manuscript in preparation

FDA Approved Analogs of Thalidomide

Thalidomide

Lenalidomide Pomalidomide
 Acknowledgement!
Lauren Aleksunes – Rutgers University
Howard McLeod – Moffitt Cancer Center
Shaunna Beedie – Oxford University
Neil Vargesson – Aberden University
Tristan Sissung – NCI/NIH
Cindy Chau – NCI/NIH
Cody Peer - NCI/NIH
Douglas K. Price – NCI/NIH
For questions, please contact
the course coordinator
Thank You!
 Course Directors

Dr. Lisa M. Cordes Dr. William Douglas Figg, Sr

PharmD, BCACP, BCOP PharmD, MBA