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Principles of Clinical Pharmacology

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Title: Principles of Clinical Pharmacology


1
Principles ofClinical Pharmacology
  • Steven P. Stratton, Ph.D.

2
Potential Therapeutic Outcomes
  • Efficacy without toxicity
  • Palliation
  • Efficacy with toxicity
  • Treatment, potentially curative
  • Toxicity without efficacy
  • Poison
  • Neither toxicity nor efficacy
  • Alternative medicine

3
Pharmacokinetics
4
Pharmacodynamics
5
Practical considerations in designing clinical
drug intervention trials
  • Why this drug?
  • What dose?
  • What schedule?
  • What combination?
  • What about other interactions?

6
Administering Drugs Things to consider
  • Age
  • Renal status
  • Liver function
  • Polymorphisms
  • Cytochrome P450 (genetics, drug interactions)
  • Acetylator status (genetics)
  • Target present?

7
Administering DrugsThings 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?
8
Audience Question 1 Once in the clinic, what
is the primary reason for failure of
experimental drugs to gain FDA approval?
  1. Toxicity
  2. Efficacy
  3. Pharmacokinetic Properties
  4. Cost
  5. Marketing

9
Reasons for Attrition During Clinical Development
50
40
30
Percentage of New Drugs Failing
20
10
0
Other
Safety
PK
Efficacy
Toxicology
Commercial
Formulation
Cost of Goods
Nature Reviews Drug Discovery 2, 566-580 (2003)
10
PK Terminology
11
Audience Question 2 What is the most
important pharmacokinetic variable?
  1. Volume of Distribution (Vd)
  2. Bioavailability (F)
  3. Clearance (CL)
  4. Half-life (t1/2)
  5. Area Under the Curve (AUC)

12
Apparent Volume of Distribution (Vd)
13
Protein Binding
  • Large fraction of drug bound to tissue
  • Unavailable for drug function
  • Easily measured in vitro ( bound)
  • Consequences
  • What if bound drug is displaced?
  • e.g. aspirin, warfarin displaces 1

Experimental Drug A 90 bound 10 free ? 11
free Free drug concentration ? 10
Experimental Drug B 99 bound 1 free ? 2
free Free drug concentration ? 100
14
Clearance (CL)
  • Renal
  • Hepatic
  • Lung

It hurts when I pee.
15
Area Under the Curve (AUC)
  • Integration of Conc. vs. Time
  • Measure of systemic exposure

16
Half-life (t½)
  • 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

t½ Vd x ln(2) / CL
17
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 schedule
  • Example doxorubicin

18
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

19
Audience Question 3 If you failed to abstain
from one of these, but had to be at work and
drug-free in one hour, which would be least
likely to result in your dismissal?
  1. 5 mg oxycodone
  2. 150 mg erlotinib
  3. Top-shelf (Patron) margarita
  4. 4-5 bong hits

20
PK/PD Modeling
21
PK Variability in Ovarian Cancer Patients250
mg/m2, 24 hr infusion, 22-23 hr sample, n 48
Cancer Chemother Pharmacol 3348-52 (1993)
22
PK/PD modeling of Taxol-induced neutropenia
  • Non-linear kinetics
  • Myelosuppression related to duration of threshold
    plasma concentration
  • Taxol 0.05 mM
  • Prediction of disposition and toxicity

Gianni et al J Clin Oncol 13180-190 (1995)
23
PK/PD ModelingEffect of formulation on
paclitaxel PK
  • 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

24
  • paclitaxel (Taxol)
  • 6 hr infusion, q 21d
  • Cremaphor formulation
  • Premedication
  • Non-linear kinetics
  • J Clin Oncology 91261-1267 (1991)
  • paclitaxel (ABI_007)
  • nanoparticles
  • 30 min infusion, q 21d
  • No cremaphor
  • No premeds
  • Linear kinetics
  • Clin Cancer Res 81038-1044 (2002)

Stratton Clin Pharm AACR/ASCO Vail 2005
25
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
  • Identification of patients predisposed to severe
    irinotecan toxicity

Innocenti et al. J Clin Oncol 221382-1388 (2004)
26
Molecularly-targeted Drugs
We found a drug. Now go find something for it
to cure.
27
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
  • EGFR signaling is implicated in angiogenesis,
    proliferation, and inhibition of apoptosis

28
EGFR Mechanism
Courtesy of Genentech
29
EGFR Targeted Therapy
  • Neutralizing monoclonal antibody
  • cetuximab
  • competitive inhibitor
  • prevents dimerization
  • Tyrosine kinase inhibitors
  • erlotinib, gefitinib
  • reversible inhibitors
  • lapatinib
  • duel EGFR/erbB2 irreversible inhibitor

30
Issues with molecularly targeted EGFR inhibitors
  • Mutation in EGFR
  • Activation of redundant pathways
  • Constitutive activation of downstream signaling
    factors

31
Altered response to EGFR inhibitors
Mutations in the EGFR gene
  • EGFR mutations have been characterized in
    gliomas, NSCLC, breast, ovarian cancers
  • Activating mutations correlated with increased
    response to gefitinib in NSCLC

32
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 11397-405 (2005)
33
Resistance to EGFR inhibitors
Constitutive activation of pathways downstream of
EGFR
Camp ER et al, Clin Cancer Res 11397-405 (2005)
34
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 are not as specific as we
    think (e.g., imatinib mesylate, sorafenib)
  • Pleiotropism

35
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 (valid) biomarker is hard to find

36
How do we improve targeted therapies?
  1. Combinations
  2. We need better tools to select the best
    patient/therapy combinations

37
Pharmacogenomics
  • How variations in the genome affect the response
    to medications

38
Practical Advice in PK Study Design
39
Typical Phase 1/PK Study
  • Goal
  • Capture adequate tissue samples to measure
    drug/metabolite levels over time
  • 0, ½, 1, 2, 4, 8, 24, 48 hr
  • Day 8, Day 15
  • Capture 4-5 half-lives if possible
  • May need to collect urine, other fluids?

40
Practical Advice in PK Study Design
  • Know your analyst
  • Ensure that the analytical technique is available
  • Ensure that the method is available, validated,
    and reliable
  • Define sample preparation
  • 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

41
Practical Advice in PK Study Design
  • Consider your patients
  • Dont exsanguinate them
  • Extended PK sampling can be exhausting
  • Dont sample from the infusion port
  • Define and monitor sample handling!!
  • Ensure study personnel are informed and
    understand SOPs
  • Shipping whole blood at room temp instead of
    frozen plasma ? Disaster
  • Cheap ink, cheap labels, and freezers dont mix

42
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