Pharmac Kinetics

P262 Pharmacokinetics
Introduction January 19, 2011
Required reading
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Tozer and Rowland text

z
Chapter 1
CLINICAL PHARMACOKINETICS and PHARMACODYNAMICS: Does It Matter?

All drugs are poisonous. Its only a matter of the dose. The Third Defense, 1537
Paracelsus: 1493-1541
What is Pharmacokinetics [PK]?
What is pharmacokinetics [PK]?

-Plot of drug C versus time - Study Design: How it was administered? Oral, single dose - To whom? A human -What is sampled, and the frequency and duration of sampling? Blood collected, often measure total plasma drug C
Drug concentration in reference fluid (plasma)
time
PK is a quantitative science
Pattern of C measurements indicate the rates of increases and decreases in C
time
Pharmacokineticists are interested to quantitate C-t data, to extract PK parameters that characterize the properties of the drug
What PK properties can we quantitate?
-Drug absorption in the GI tract

-Drug distribution -Drug metabolism -Drug excretion
ADME
time
Absorption
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Process by which drug proceeds from the site of administration to a site of measurement in body For absorption to occur, drug must cross a membrane to reach blood Rate of absorption Extent of absorption
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Distribution
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Distribution of drug from blood to intra- and extra-cellular fluids Blood carrying absorbed drug to the rest of the body is referred to as systemic circulation Distribution is reversible Rate and extent of distribution
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Elimination
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Irreversible loss of drug from body Blood carries drug to organs of elimination Two processes:
Metabolism z Excretion
z
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Metabolism
z z
Enzymes mainly present in liver Other eliminating organs: GI tract, lung, kidney, skin
Excretion
z z
The kidney is the most important organ for excreting drugs and metabolites Substances excreted in feces mainly unabsorbed drug or drug / metabolite secreted into bile
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What does the drug concentration-time plot represent?

Look inside the system to depict ADME. -Dynamic processes change over time, can use rate equations to characterize.
Drug at absorption site Percent of Dose
100
50
Drug in body
-ADME processes are occurring simultaneously rather than sequentially. At any one time, Excreted metabolite one process may be dominant.
Excreted drug
- However, each drug molecule has a unique sequential path in the body.
Metabolite in body
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Time
TISSUES
4
SYSTEMIC 3 CIRCULATION
Track sequential path of each drug and/or metabolite molecule in body. Rate of each process [1 thru 5] determine PK parameters and pattern of data or shape of C-t curve.
1
GUT
2
LIVER
Drug excreted
5
Metabolite excreted GI elimination 5/10 drug is absorbed 2/10 drug is unabsorbed 3/8 drug is metabolized 4/5 drug distributes 2/3 metabolite distributes 5/5 drug is excreted 3/3 metabolite is excreted
4
TISSUES
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Plasma C-t profiles
Single Oral Dose IV Bolus
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IV Infusion
Intermittent Infusion Multiple Dosing
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Approaches to PK Data Analysis

-Nature of PK analysis is dependent on what is measured and route of administration. -In most clinical PK studies, plasma drug Cs are available, possibly urine. - In this example of oral administration, what PK parameters can be obtained?
C
AUC
- Cmax, Cmin, AUC = area under the plasma drug concentration-time curve, and elimination half-life. -Parameters obtained by either compartmental or noncompartmental methods.
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Compartmental Model Approach to Data Analysis
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-In compartmental analysis we superimpose or apply a mathematical model to the measured 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 observed Cs; C = f(t). C is a function of time. The value of C is dependent on time. The model equation produces the curve. - From the model equation, we can calculate PK parameters such as AUC, and the elimination half-life [t1/2].
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Noncompartmental Approach to Data Analysis
Cmax
-NC analysis is also referred to as

model-independent analysis, and as implied is not concerned with fitting a model to the observed Cs. -Apply mathematical techniques to extract PK parameters.
Cmin
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Summary Introduction to PK
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PK is the study of ADME

z
Dynamic processes that occur simultaneously and can be cast into rate equations, the solution of which gives C = f(t).
PK data analysis consists of noncompartmental and compartmental modeling techniques that extract PK parameters
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ADME Properties
Oral dose
Solubility pH stability
Absorption
Phys.chem properties e.g. Predicted LogP HIA- Passive Absorption GI Metabolism by CYP3A4 Transporters e.g. Pgp
Hepatic clearance
P450 Metabolism: CYP3A4 Regioselectivity/Lability Reactive Intermediate Formation Non-P450 based e.g. UGTs Biliary (active & passive)
P450 Inhibition and induction
Distribution
Blood-Brain Barrier Plasma protein binding Transporters Volume of distribution
The Bucket
Although pharmacokinetics has a complex origin,

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most important concepts can be explained with a bucket.
Is pharmacokinetics important?
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Critical component of preclinical and clinical drug development programs z Regulatory necessity that hopefully leads to rational design of drug dosing regimens Integral component of experimental therapeutics research z PK/PD, pharmacogenetics/polymorphisms, drug delivery to tissues, targeted therapeutics Clinical PK/PD; drug dosage design, individualized regimens based on covariates PK information is a stalwart of a pharmacists expertise
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Pharmacokinetics in Drug Discovery and Development

Predicting human PK from in vitro data Predicting human PK from animal data Measuring human PK Population PK
Lead Optimization
Candidate Selection
Early Development
FIM
POC
Late Development
= Compound synthesis
= Compound testing
ADME Properties
Oral dose
Solubility pH stability
Absorption
Phys.chem properties e.g. Predicted LogP HIA- Passive Absorption GI Metabolism by CYP3A4 Transporters e.g. Pgp
Hepatic clearance
P450 Metabolism: CYP3A4 Regioselectivity/Lability Reactive Intermediate Formation Non-P450 based e.g. UGTs Biliary (active & passive)
P450 Inhibition and induction
Distribution
Blood-Brain Barrier Plasma protein binding Transporters Volume of distribution
Is Pharmacokinetics Important?
Ref - Peter Van Osta, MD, 2010
Failures due to unfavorable PK properties (poor bioavailability, rapid clearance, etc.) have been decreased due to better experiments and interpretation.
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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 regimens z Understanding variability due to: z Age (pediatric, adult, elderly) z Genetic variation z Diet z Drug-drug interactions
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Dosing outside of the Therapeutic Window

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Under-dosing z Resistance antimicrobials z Pregnancy birth control pills z Pain analgesics z Stroke anticoagulants z Etc. Overdosing z Any number of toxicities z Death
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Gentamicin dosing in neonates

Elevated peak (>12 mg/L) can cause ototoxicity Elevated 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
Zero-Order Elimination Kinetics

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Question: When consuming alcohol, why do things go so bad so quickly? Answer: Zero-order elimination kinetics z Most drugs are eliminated faster at higher drug concentrations z Alcohol metabolism is quickly saturated, resulting in zero-order kinetics. Consumption at rates greater than elimination results in rapid and continuous increases in alcohol levels.
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P262 Pharmacokinetics

Introduction January 19, 2011

Tozer and Rowland text

CLINICAL PHARMACOKINETICS and PHARMACODYNAMICS: Does It Matter?

What is Pharmacokinetics [PK]?

What is pharmacokinetics [PK]?

Drug concentration in reference fluid (plasma)

Drug concentration in reference fluid (plasma)

What PK properties can we quantitate?

-Drug absorption in the GI tract

-Drug distribution -Drug metabolism -Drug excretion

What does the drug concentration-time plot represent?

Plasma C-t profiles

Single Oral Dose IV Bolus

Intermittent Infusion Multiple Dosing

Approaches to PK Data Analysis

Compartmental Model Approach to Data Analysis

Noncompartmental Approach to Data Analysis

-NC analysis is also referred to as

PK is the study of ADME

P450 Inhibition and induction

Although pharmacokinetics has a complex origin,

most important concepts can be explained with a bucket.

Pharmacokinetics in Drug Discovery and Development

P450 Inhibition and induction

Ref - Peter Van Osta, MD, 2010

Essence of Clinical PK - Design of Drug Dosing Regimens

Dosing outside of the Therapeutic Window

Gentamicin dosing in neonates

Zero-Order Elimination Kinetics

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