Introduction

Clinical Pharmacology

Prof. Dr. dr. M.T. Kamaluddin, M.Sc., SpFK

Department of Pharmacology, Medical Faculty

Sriwijaya University

2017
Learning Objectives in Clinical
Pharmacology :
Define Pharmacokinetics & Pharmacodynamics
Identify PK/PD approaches, terminology, and
parameters
Recognize and develop endpoints for PK/PD
modeling
Identify barriers to molecularly targeted drugs
Understand practical considerations in design of PK
studies in clinical protocols
Pharmacology is the study of drugs (chemicals) that
alter functions of living organisms.

CLINICAL PHARMACOLOGY is the use of drugs in

human :
to prevent, diagnose, or treat signs, symptoms, and
disease processes.

When prevention or cure is not a reasonable goal,

relief of symptoms can greatly improve quality of
life and ability to function in activities
of daily living.
Clinical Pharmacology?
Potential Therapeutic Outcomes

Efficacy without toxicity

Palliation
Efficacy with toxicity
Treatment, potentially curative
Toxicity without efficacy
Poison
Neither toxicity nor efficacy
Alternative medicine
Pharmacokinetics

80 mg/m2
PT 004

Plasma Concentrations (g/ml)

10 PT 005
PT 006
8 PT 007
LOQ
6

0 100 200 300 400 500

Time (min)
PHARMACOKINETICS
Pharmacokinetics involves drug movement through the body
(ie, what the body does to the drug) to reach sites of
action,metabolism, and excretion.

Specific processes are absorption, distribution, metabolism

(biotransformation), and excretion.

Overall, these processes largely determine serum drug levels,

onset, peak and duration of drug actions, drug half-life, therapeutic
and adverse drug effects, and other important aspects
of drug therapy.
Pharmacokinetics
Sustained-release tablets
Advantages
Extended-release products offer 3 potential
benefits:
sustained blood levels
attenuation of adverse effects
improved patient compliance.
 Sustained blood levels

The size and frequency of

dosing is determined by the
pharmacodynamic and
pharmacokinetic properties of
the drug. The slower the rate
of absorption, the less the
blood concentrations fluctuate
within a dosing interval. This
enables higher doses to be
given less frequently. For
drugs with relatively short
half-lives, the use of extended-
release products may
maintain therapeutic
concentrations over
prolonged periods
Improved patient compliance
Drugs with short half-lives often need to be given
at frequent intervals to maintain blood
concentrations within the therapeutic range.
There is an inverse correlation between the
frequency of dosing and patient compliance.
A reduction in the number of daily doses offered
by extended-release products has the potential to
improve compliance.3
However, this advantage probably only occurs
when conventional formulations need to be given
3 or more times a day.
 Sustained-release tablets
Disadvantages
For many controlled-release products, the release rate can be
altered by various factors including food and the rate of transit
through the gut. There may be some differences in the release rate
from one dose to another, but these have been minimised by
modern formulations.
Extended-release products contain a higher drug load and thus
any loss of integrity of the release characteristics of the dosage
form has potential problems. While some extended-release
products can be divided to provide half-doses, others should only
be taken whole. Modified-release products should never be
crushed or chewed as the slow-release characteristics may be lost
and toxicity may result. This is particularly important in patients
unable to swallow whole tablets, a problem commonly affecting the
elderly. The larger size of extended-release products may cause
difficulties in ingestion or transit through the gut. These problems
may result in some drugs, e.g. Slow-K, causing local tissue damage
in patients who have a pathological or drug-induced reduction in
gut motility.
Oral drugs
Other medications have objectionable tastes
and are sugar-coated to improve tolerability.
If this type of medication is crushed, the
patient would be subject to its unpleasant
taste, which could significantly impair
medication adherence. Additionally, both
sublingual and effervescent medications
should not be crushed because it will
decrease the medications effectiveness.
Pharmacodynamics
 Practical considerations in designing clinical
drug intervention trials

Why this drug?

What dose?
What schedule?
What combination?
What about other interactions?
Administering Drugs: Things to
consider
Age
Renal status
Liver function
Polymorphisms
Cytochrome P450 (genetics, drug interactions)
Acetylator status (genetics)
Target present?
Administering Drugs:
Things to consider
What should I measure?
How do I measure it?
Correct sampling schedule
Validated method available?

and most importantly

What do I do with the answer?

 Reasons for Attrition During Clinical Development

Percentage of New Drugs Failing 50

40

30

20

10

Nature Reviews Drug Discovery 2, 566-580 (2003)

Apparent Volume of Distribution (Vd)

Amt of DrugAmt
(dose)
of Drug (dose)
VConcentration
d= =
Concentration Vd

Small Vd
Low tissue binding Large Vd
Drug tightly bound
Clearance (CL)

Elimination Rate
CL =
Concentration

It hurts when I pee.

Area Under the Curve (AUC)

AUC
Integration of
Conc. vs. Time

Measure of

systemic exposure
Half-life (t)
Time required to clear 50%
of drug
Depends on Volume of
Distribution (Vd) and
Clearance (CL)
Multi-phasic (if you can
capture the distribution
phase)
Rule of Thumb: Drug is
cleared in 5 half-lives
t = Vd x ln(2) / CL
Other Important Parameters
Peak plasma concentration
Bioavailability
Duration above a threshold concentration
Free drug vs. total drug
Cumulative dose
Bioactivation to active metabolite
Plasma protein binding
 PK Analysis
Linear Pharmacokinetics
First order kinetics
Covers most drugs
Rate of change depends only
on the current [drug]
Half-life remains constant no
matter how high the
concentration
AUC not affected by
dC
schedule = -kC
dt
Example: doxorubicin
PK Analysis
Non-Linear Pharmacokinetics (zero order)
Classic examples: ethanol, phenytoin
Saturable metabolism
Decreased CL at higher doses
Shortened infusion increased AUC
Examples: 5-FU, Taxol

Saturable absorption
Decreased proportional AUC at higher doses
Lengthened infusion increased plasma conc.
Examples: methotrexate, cisplatin
PK/PD Modeling
 PK Variability in Ovarian Cancer Patients
250 mg/m2, 24 hr infusion, 22-23 hr sample, n = 48

Lowered
efficacy Myelosuppression

Cancer Chemother Pharmacol 33:48-52 (1993)

 PK/PD modeling of Taxol-
induced neutropenia
Non-linear kinetics

Myelosuppression related to
duration of threshold plasma
concentration
[Taxol] 0.05 M

Prediction of disposition and

toxicity

Gianni et al J Clin Oncol 13:180-190 (1995)

 PK/PD Modeling (paclitaxel)
First-Order Elimination (Abraxane)
Rate of elimination is proportional to
drug concentration
Constant fraction of drug eliminated
per unit time
Zero-Order Elimination (Taxol)
Rate of elimination constant
regardless of drug concentration
Constant amount of drug eliminated
per unit time
 paclitaxel (Taxol)
6 hr infusion, q 21d
Cremaphor formulation
mg/m2
Premedication
275

250 mg/m2
Non-linear kinetics
175 mg/m2

J Clin Oncology 9:1261-1267 (1991)

paclitaxel (ABI_007)
nanoparticles
30 min infusion, q 21d
No cremaphor
No premeds
Linear kinetics

Clin Cancer Res 8:1038-1044 (2002)

Stratton Clin Pharm AACR/ASCO Vail 2005
 PD Modeling Example: Pharmacogenetics
Myelotoxicity and UGT genetic polymorphisms

Irinotecan
350 mg/m2
90 min infusion, q3w
n = 66

SN-38 metabolism dependent

on UGT variant
Grade 4
Identification of patients
predisposed to severe
irinotecan toxicity

Innocenti et al. J Clin Oncol 22:1382-1388 (2004)

Molecularly-targeted Drugs

We found a drug. Now go find something for it to cure.

 Shift Towards Target-based vs.
Compound-based Development
Compound-based (backward)
Interesting compound discovered with activity
in in vitro models

Target-based (forward)
Protein or gene targets identified on
carcinogenesis pathway.
Drugs designed to interfere with these specific
targets
Compound-based vs. Target-based Drug
Development
Compound-Based Target-Based

Compound isolated Target identified

Compound screened in cell culture Target validated in vitro

Activity in Animal Models Compounds screened for

target selectivity
Mechanism Toxicology
Toxicology performed
Clinical Trials
Phase I Phase I, II, III Clinical Trials
in Patients Expressing Target
Phase II

Phase III
EGFR as a Molecular Target
Member of erbB family of receptor tyrosine
kinases
EGFR (ErbB1), HER2/Neu (ErbB2), HER3 (ErbB3)
and HER4 (ErbB4)

Overexpressed in various solid tumors

Overexpression has been correlated with poor
prognosis

EGRF signaling is implicated in angiogenesis,

proliferation, and inhibition of apoptosis
 EGFR Mechanism

Extracellular glycosylated ligand

binding domain
Transmembrane domain with
hydrophobic anchor
Catalytic tyrosine kinase domain
C-terminal end contains tyrosine
residues phosphorylated upon
ligand binding
Dimerizes (homo or hetero)
upon ligand binding

Courtesy of Genentech
EGFR Targeted Therapy
Neutralizing monoclonal antibodies
cetuximab (Erbitux), a competitive inhibitor that
prevents dimerization

Tyrosine kinase inhibitors

gefitinib (Iressa), erlotinib (Tarceva)
reversible inhibitors
GW572016 (lapatinib)
duel EGFR/erbB2 irreversible inhibitor
Forms covalent bonds with the cysteine residues in the ATP
binding site
Altered response to EGFR inhibitors

Mutations in the EGFR gene

EGFR mutations have been characterized in
some solid tumors including gliomas, non-small
cell ling cancer, breast and ovarian cancers

Activating mutations of EGFR correlate with

increased responsiveness to gefitinib in non-
small cell lung cancer
 Resistance to EGFR inhibitors

Activation of redundant pathways

Resistance caused by activation of other tyrosine kinase receptors that

bypass the EGFR pathway

Camp ER et al, Clin Cancer Res 11:397-405 (2005)

 Resistance to EGFR inhibitors

Constitutive activation of pathways downstream of EGFR

Activating mutations in
genes downstream of
EGFR signaling could
bypass the effect of the
EGFR inhibitor

Camp ER et al, Clin Cancer Res 11:397-405 (2005)

Resistance to EGFR inhibitors

Ligand-independent activation of EGFR

EGFR can be activated by interaction with

integrins

Urokinase plasminogen activator (uPA) can

activate Erk via the a5b1 integrin
Cetuximab could not inhibit this pathway
 Summary: Issues with molecularly targeted
EGFR inhibitors

Mutation in EGFR
Activation of redundant pathways
Constitutive activation of downstream
signaling factors
Ligand-independent activation of EGFR
Concerns with Targeted Therapy

The Butterfly effect

Predicting toxicities of a single target is difficult when the target of
interest is relatively upstream in a pathway
Example: bortezomib (Velcade) myelosuppression, fatigue, etc.

Dosing regimens are difficult to determine

High potency difficult detection of drug
Cytostatic mechanism low toxicity, MED vs. MTD

Targeted therapies may not be as specific as we think

(e.g., imatinib mesylate)
Pleiotropism
Concerns with Targeted Therapy (contd)
Redundancy
Cells that find a way get rewarded and select for
resistance

Delivery (chemistry)
The drug may not reach the target in vivo (PK)

Bogus mechanism
Almost all in vitro mechanisms are convenient to
believe once the xenograft data is positive
A good biomarker is hard to find
Practical Advice in PK Study Design
 Practical Advice in PK Study Design
(contd)
Regulatory Considerations Patient Considerations

Its a baby. Federal regulations prohibit our

mentioning its race, age, or gender. I was hoping I could choose my own doctor
 Practical Advice in PK Study Design
(contd)
Dont perform PK unless you know what to do with
the answer
Capture adequate data (4-5 half lives95% elimination)

Know your sample size

The biometrist is your friend
visit them early and often

Be kind to nurses
Do you really want that 16 hr PK?
Dont require a sample at the end of the infusion- too many
things at once is trouble
 Practical Advice in PK Study Design
(contd)
Consider your patients
Dont exsanguinate
Extended PK sampling can be exhausting
Dont sample from the infusion port

Define and monitor sample handling!!

Shipping whole blood at room temp instead of frozen plasma
Disaster
Cheap ink, cheap labels, and freezers dont mix
 PHARMACODYNAMICS
Pharmacodynamics involves drug actions on target
cells and the resulting alterations in cellular biochemical
reactions and functions (ie, what the drug does to the
body).

As previously stated, all drug actions occur at the

cellular level.
Pharmacodynamics
Plasma proteins, mainly albumin (A), act as carriers for
drug molecules (D).
Bound drug (AD) stays in bloodstream and is pharmacologically
inactive.
Free drug (D) can leave the bloodstream and act on body cells.
 Pharmacodynamic Variables
Maximum Effect (ll pharmacologic responses must have a
maximum effect (Emax). No matter how high the drug
concentration goes, a point will be reached beyond which no
further increment in response is achieved.

Sensitivity (the sensitivity of the target organ to drug concentration

is reflected by the concentration required to produce 50% of
maximum effect, the EC50. Failure of response due to diminished
sensitivity to the drug can be detected by measuringin a patient
who is not getting betterdrug concentrations that are usually
associated with therapeutic response. This may be a result of
abnormal physiologyeg, hyperkalemia diminishes
responsiveness to digoxinor drug antagonismeg, calcium
channel blockers impair the inotropic response to digoxin.
Pharmacodynamic Variables (contd)

Clearance is the single most important

factor determining drug concentrations.
Clearance is readily estimated from the
dosing rate and mean steady-state
concentration. Blood samples should be
appropriately timed to estimate steady-state
concentration.
SERUM HALF-LIFE (T1/2)

Serum half-life, also called elimination half-life, is the time required for the
serum concentration of a drug to decrease by 50%.

It is determined primarily by the drugs rates of metabolism and excretion. A

drug with a short half-life requires more frequent administration than one
with a long half-life.
When a drug is given at a stable dose, four or five halflives are required to achieve
steady-state concentrations and develop equilibrium between tissue and serum
concentrations.

Because maximal therapeutic effects do not occur until equilibrium is

established, some drugs are not fully effective for days or weeks.
To maintain steady-state conditions, the amount of drug given must equal the
amount eliminated from the body.
When a drug dose is changed, an additional four to five halflives are required to
re-establish equilibrium; when a drug is discontinued, it is eliminated
gradually over several half-lives.
ioavailability is defined as the fraction of a
given drug dose that reaches the circulation
in unchanged form and becomes available
for systemic distribution. The larger the
presystemic elimination, the smaller is the
bioavailability of an orally administered
drug.
ll membrane contains receptors for physiologic substances
such as hormones (H) and neurotransmitters (NT). These
substances stimulate or inhibit cellular function.
Drug molecules (Da and Db) also interact with receptors to
stimulate or inhibit cellular function
 Drug-Related Variables
Dosage
Route of Administration
DrugDiet Interactions
DrugDrug Interactions:
Increased Drug Effects (Additive effects, Synergism or
potentiation, Interference by one drug with the metabolism
or elimination of a second drug, Displacement of one drug
from plasma protein-binding sites by a second drug
increases the effects of the displaced drug)
Decreased Drug Effects - Interactions in which drug effects
are decreased are grouped under the term antagonism
(Example: naloxone (a narcotic antagonist) + morphine (a narcotic or
opioid analgesic) >relief of opioidinduced respiratory depression.
Naloxone molecules displace morphine molecules from their receptor
sites on nerve cells in the brain so that the morphine molecules cannot
continue to exert their depressant effects.
 Client-Related Variables
Age
Body Weight
Genetic and Ethnic Characteristics
Gender (xcept during pregnancy and
lactation, gender has been considered a
minor influence on drug action).
Pathologic Conditions
Psychological Considerations
 ADVERSE EFFECTS OF DRUGS
he term adverse effects refers to any undesired responses to drug
administration, as opposed to therapeutic effects, which are desired
responses.
Some adverse effects occur with usual therapeutic doses
of drugs (often called side effects); others are more likely to
occur and to be more severe with high doses.
CNS effects may result from CNS stimulation (eg,
agitation,confusion, delirium, disorientation,
hallucinations,psychosis, seizures) or CNS depression
(dizziness, drowsiness, impaired level of
consciousness,sedation, coma, impaired respiration and
circulation).
Gastrointestinal effects (anorexia, nausea, vomiting, constipation,
diarrhea)
Hematologic effects (blood coagulation disorders, bleeding
disorders, bone marrow depression, anemias, leukopenia,
agranulocytosis, thrombocytopenia)
 ADVERSE EFFECTS OF DRUGS
Hepatotoxicity (hepatitis, liver dysfunction or failure, biliary tract
inflammation or obstruction)
Nephrotoxicity (nephritis, renal insufficiency or failure)
Hypersensitivity or allergy
Drug fever
Idiosyncrasy refers to an unexpected reaction to a drug that
occurs the first time it is given.
Drug dependence
Carcinogenicity is the ability of a substance to cause cancer.
Teratogenicity is the ability of a substance to cause abnormal
fetal development when taken by pregnant women.

Drug toxicity (also called poisoning, overdose, or intoxication)

results from excessive amounts of a drug and may
cause reversible or irreversible damage to body tissues.
 Attenuation of adverse effects
With conventional dosage forms, high peak blood
concentrations may be reached soon after administration
with possible adverse effects related to the transiently high
concentration.
Example : hypertensive patients taking rapid-release nifedipine products.

The use of an extended-release product avoids the high

initial blood concentrations which cause the sudden
reduction in blood pressure and other significant
haemodynamic changes such as reflex tachycardia.1
Example :
is the transient nausea at sub-toxic concentrations which results from the
local irritation caused by high intestinal concentrations of some
conventional-release products such as theophylline.
 Thank you
I just of being collaps