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P262 PharmacokineticsIntroduction
J anuary 19, 2011
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Required reading
|Tozer and Rowland text
z Chapter 1
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CLINICAL PHARMACOKINETICS andPHARMACODYNAMICS: Does It Matter?
Paracelsus: 1493-1541
All drugs are poisonous.
Its only a matter of thedose.
The Third Defense, 1537
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What is Pharmacokinetics [PK]?
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What is pharmacokinetics [PK]?-Plot of drug C
versus time
- Study Design:How it wasadministered?Oral, single dose
-To whom? Ahuman
-What issampled, and thefrequency and
duration ofsampling? Bloodcollected, oftenmeasure total
plasma drug C
Drugcon
centration
in
reference
fluid(plasm
a)
time
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Pattern of Cmeasurementsindicate the rates of
increases anddecreases in C
Pharmacokineticistsare interested toquantitate C-t data, toextract PK parameters
that characterize theproperties of the drug
PK is a quantitative science
Drugcon
centration
in
reference
fluid(plasm
a)
time
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What PK properties can we quantitate?
-Drug absorption in theGI tract
-Drug distribution
-Drug metabolism
-Drug excretion
ADME
Drugconc
entrationin
referencefluid(plasma)
time
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Absorption| Process by which drug proceeds from the
site of administration to a site ofmeasurement in body
| For absorption to occur, drug must cross amembrane to reach blood
| Rate of absorption
| Extent of absorption
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Distribution
| Distribution of drug from blood tointra- and extra-cellular fluids
| Blood carrying absorbed drug to the
rest of the body is referred to assystemic circulation
| Distribution is reversible
| Rate and extent of distribution
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Elimination
| Irreversible loss of drug from body
| Blood carries drug to organs of
elimination
|Two processes:
z Metabolism
z Excretion
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|
Metabolismz Enzymes mainly present in liver
z Other eliminating organs: GI tract, lung,
kidney, skin
| Excretion
zThe kidney is the most important organ forexcreting drugs and metabolites
z Substances excreted in feces mainly
unabsorbed drug or drug / metabolitesecreted into bile
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What does the drug concentration-time plot
represent?
Time
PercentofDose
Drug at absorption site
Drug in body
100
50
Excreted drug
Metabolite in body
Excreted metabolite
Look inside the systemto depict ADME.
-Dynamic processes change
over time, can use rateequations to characterize.
-ADME processes are occurring
simultaneously rather thansequentially. At any one time,one process may be dominant.
- However, each drug moleculehas a unique sequential pathin the body.
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GUTLIVER
SYSTEMICCIRCULATION
GI elimination
TISSUES
TISSUES
Drug
excreted
Metabolite
excreted
1155
33
22
44
44
55
Track sequential path ofeach drug and/or metabolitemolecule in body.
Rate of each process [1 thru 5]determine PK parameters andpattern of data or shape ofC-t curve.
5/10 drug is absorbed 2/10 drug is unabsorbed
3/8 drug is metabolized 4/5 drug distributes 2/3 metabolite distr ibutes 5/5 drug is excreted
3/3 metabolite is excreted
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Plasma C-t profiles
IV BolusSingle Oral Dose
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Intermittent Infusion
IV Infusion
Multiple Dosing
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-Nature of PK analysis is dependent
on what is measured and route ofadministration.
-In most clinical PK studies, plasma
drug Cs are available, possibly urine.
- In this example of oral administration,what PK parameters can be obtained?
- Cmax, Cmin, AUC = area under theplasma drug concentration-time curve,and elimination half-life.
-Parameters obtained by eithercompartmental or noncompartmentalmethods.
Approaches to PK Data Analysis
C
t
AUC
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Compartmental Model Approach to
Data Analysis
-In compartmental analysiswe superimpose or apply amathematical model to themeasured C-t data. Typically,
fit a model to the data.
- A model is an equation[s],based on a set of assumptions,
which describes the observedCs; C = f(t). C is a function oftime. The value of C isdependent on time. The model
equation produces the curve.
- From the model equation, wecan calculate PK parameters
such as AUC, and theelimination half-life [t1/2].
1 kka
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-NC analysis is also referred to asmodel-independent analysis, andas implied is not concerned withfitting a model to the observed
Cs.
-Apply mathematical techniquesto extract PK parameters.
Noncompartmental Approach to
Data Analysis
Cmax
Cmin
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Summary Introduction to PK
| PK is the study of ADME
z
Dynamic processes that occursimultaneously and can be cast intorate equations, the solution of which
gives C = f(t).
| PK data analysis consists ofnoncompartmental andcompartmental modeling techniques
that extract PK parameters
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ADME Properties
Hepatic clearance
P450 Metabolism: CYP3A4
Regioselectivity/Lability
Non-P450 based
e.g. UGTs
Biliary
(active & passive)
Distribution
Blood-Brain Barrier Plasma protein binding Volume of distributionTransporters
Absorption
Phys.chem properties
e.g. Predicted LogP
HIA- Passive
Absorption
GI Metabolism by
CYP3A4
Transporters
e.g. Pgp
Oral dose
Solubility pH stability
P450 Inhibi tion and inductionReactive Intermediate Formation
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The Bucket
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Although pharmacokineticshas a complex origin,
most important concepts canbe explained with a bucket.
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Is pharmacokinetics important?| Critical component of preclinical and clinical
drug development programsz Regulatory necessity that hopefully leads to
rational design of drug dosing regimens
| Integral component of experimentaltherapeutics research
z PK/PD, pharmacogenetics/polymorphisms,drug delivery to tissues, targetedtherapeutics
| Clinical PK/PD; drug dosage design,individualized regimens based on covariates
|
PK information is a stalwart of a pharmacistsexpertise
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Pharmacokinetics in Drug
Discovery and Development
CandidateSelection EarlyDevelopment FIM POCLead Optimization LateDevelopment
Predicting human PK
from in vitro dataMeasuring human PK
= Compound synthesis
= Compound testing
Population PKPredicting human PK
from animal data
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ADME Properties
Hepatic clearance
P450 Metabolism: CYP3A4
Regioselectivity/Lability
Non-P450 based
e.g. UGTs
Biliary
(active & passive)
Distribution
Blood-Brain Barrier Plasma protein binding Volume of distributionTransporters
Absorption
Phys.chem properties
e.g. Predicted LogP
HIA- Passive
Absorption
GI Metabolism by
CYP3A4
Transporters
e.g. Pgp
Oral dose
Solubility pH stability
P450 Inhibi tion and inductionReactive Intermediate Formation
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Is Pharmacokinetics
Important?
Failures due to unfavorable PK properties (poor bioavailability,rapid clearance, etc.) have been decreased due to betterexperiments and interpretation.
Ref - Peter Van Osta, MD, 2010
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Essence of Clinical PK - Design of
Drug Dosing Regimens
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Pharmacokinetic Variability
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| Designing optimum therapeutic regimensz Understanding variability due to:
z Age (pediatric, adult, elderly)
z Genetic variationz Dietz Drug-drug interactions
i id f h
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Dosing outside of the
Therapeutic Window
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| Under-dosingz Resistance antimicrobialsz Pregnancy birth control pills
z Pain analgesicsz Stroke anticoagulantsz Etc.
z Overdosing
z Any number of toxicitiesz Death
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Gentamicin dosing in neonates
Elevated peak (>12 mg/L) can cause ototoxicityElevated trough (>1 mg/L) can cause nephrotoxicity
Table 1. Weight-Based, Extended-Interval Gentamicin
Dosing Protocol
Birth Weight Protocol< 1250 g 4 mg/kg i.v. q48h
1250 g + indomethacin 4 mg/kg i.v. q48h
1250 g 4 mg/kg i.v. q24h
Z O d Eli i ti
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Zero-Order Elimination
Kinetics
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| Question: When consuming alcohol, why do things go so
bad so quickly?
z Answer: Zero-order elimination kineticsz Most drugs are eliminated faster at higher drug
concentrationsz Alcohol metabolism is quickly saturated, resulting in
zero-order kinetics. Consumption at rates greater thanelimination results in rapid and continuous increases inalcohol levels.