INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS
OBJECTIVES •
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To define drug product and biopharmaceutics. Describe how the principles of biopharmaceutics can affect drug product performance. Define pharmacokinetics and describe how pharmacokinetics is related to pharmacodynamics and drug toxicity. toxicity. Define pharmacokinetic model and list the assumptions that are used in developing a pharmacokinetic model
OBJECTIVES •
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To define drug product and biopharmaceutics. Describe how the principles of biopharmaceutics can affect drug product performance. Define pharmacokinetics and describe how pharmacokinetics is related to pharmacodynamics and drug toxicity. toxicity. Define pharmacokinetic model and list the assumptions that are used in developing a pharmacokinetic model
DRUG PRODUCT PERFORMANCE •
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The release of the drug substance from the drug product either for local drug action or for drug absorption into the plasma for systemic therapeutic activity. Safe, more effective and convenient to the patient.
BIOPHARMACEUTICS
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Examines the interrelationship of the physical/chemical properties of the drug, the dosage form (drug product) in which the drug is given, and the route of administration on the rate and extent of systemic absorption.
Absorption
Drug release and dissolution
Drug in the systemic circulation
Drug in the tissue
Excretion and Metabolism
Pharmacologic or clinical effect
Elimination
RELATIONSHIP BETWEEN THE DRUG, THE PRODUCT AND PHARMACOLOGIC EFFECT
MINIMUM EFFECTIVE CONCENTRATION •
The administered drug reach its site of action
BIOPHARMACEUTICS CONSIDERATIONS IN PRODUCT DESIGN ITEMS
CONSIDERATION
THERAPEUTIC OBJECTIVE
Drug is intended for rapid relief of symptoms, slow extended action given once per day (week or longer), or chronic use, is drug for local or systemic effect.
DRUG
Physical chemical properties of API, including solubility, polymorphic form, particle size.
ROUTE OF ADMINISTRATION
Oral, topical, parenteral, transdermal, inhalation etc.
DRUG DOSAGE AND DOSAGE REGIMEN
Large or small drug dose, frequency of doses, patent acceptance of drug product, patient compliance
TYPE OF DRUG PRODUCT
Orally disintegrating tablets, immediate release tablets, extended release tablets, transdermal, topical, parenteral, implant, etc.
EXCIPIENTS
Although very little pharmacodynamics activity, excipients affect drug product performance including release from drug product
METHODS OF MANUFACTURE
Variables in manufacturing process, including weighing, blending, release testing, sterility.
BIOPHARMACEUTIC FACTORS •
The design of the drug product
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Stability of the drug within the drug product
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The manufacture of the drug product
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The release of the drug from the drug product
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The rate of dissolution/release of the drug at the absorption site
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Delivery of drug to the site of action
IN-VITRO AND IN-VIVO METHODS IN-VITRO –
are procedures employing test apparatus and equipment without involving laboratory animals or humans.
IN-VIVO –
are more complex studies involving human subjects and laboratory animals.
Assess
the impact of the physical and chemical properties of the drug, drug stability and large scale production of the drug and drug product for biological performance of the drug.
PHARMACOKINETICS •
Is the science of the kinetics of the drug ADME.
•
DISPOSITION – DME or DEl
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Important prerequisite for determination or modification of dosing regimens for individuals and group patients.
STATISTICAL METHODS •
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Used for pharmacokinetic parameter estimation and data interpretation ultimately for the purpose of designing and predicting optimal dosing regimens for individuals or groups of patients. Determine data error and structural model deviation
CLINICAL PHARMACOKINETICS •
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Application of pharmacokinetic methods to drug therapy. Optimized dosing strategies based on the patients disease state and patient specific considerations. POPULATION PHARMACOKINETICS – study of the pharmacokinetic differences of drugs in various population groups. Applied in therapeutic monitoring (optimize efficacy and prevent any adverse toxicity) Drug with NTI – Monitor the plasma concentration of the patient (theophylline), monitor specific pharmacodynamics endpoint (warfarin –PTT).
PRACTICAL FOCUS: RELATIONSHIP OF DRUG CONCENTRATIONS TO DRUG RESPONSE TOXIC POTENTIALLY TOXIC
THERAPEUTIC POTENTIALLY SUBTHERAPEUTIC SUBTHERAPEUTIC
PHARMACODYNAMICS •
Refers to the relationship between the drug concentration at the site of action (receptor) and pharmacologic response (biochemical and physiologic effects that influence interaction of drug to the receptor.
DRUG EXPOSURE AND DRUG RESPONSE •
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DRUG EXPOSURE – refers to the dose (drug input into the body) and various measures of acute or integrated drug concentrations in plasma and other biological fluid (Cmax, Cmin, Css, AUC) DRUG RESPONSE – refers to the direct measure of the pharmacologic effect of the drug. Clinically remote biomarkers (receptor occupancy), •
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presumed mechanistic effect (ACE inhibition), potential accepted surrogate (effects on blood pressure, lipid and cardiac output) full range of short-term or long-term clinical effects related to either efficacy or safety
TOXICOKINETICS AND CLINICAL TOXICOLOGY •
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TOXICOKINETICS – application of pharmacokinetic principles to the design, conduct and interpretation of drug safety evaluation studies and validating doserelated exposure in animals. Aid in the interpretation of toxicologic findings in animals and exploration resulting to data to humans CLINICAL TOXICOLOGY - study of the adverse effects of drugs and toxic substances (poisons) in the body.
MEASUREMENT OF DRUG CONCENTRATIONS •
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BIOLOGICAL SAMPLES (milk, saliva, plasma and urine) Chromatographic and mass spectrometric methods are most frequently employed in drug concentration measurement. Chromatography – separates the drug from other related materials that may cause assay interference. Mass spectroscopy – allows detection of molecules or molecule fragments based on their mass to charge ratio.
SAMPLING •
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INVASIVE – sampling blood, spinal fluid, synovial fluid, tissue biopsy or any biological material that requires parenteral or surgical intervention in the patient. NON-INVASIVE – sampling of urine, saliva, feces, expired air, or any biological material that can be obtained w/o parenteral or surgical intervention.
BLOOD COMPONENT
HOW OBTAINED
COMPONENTS
WHOLE BLOOD
Whole blood is generally obtained by venous puncture and contains an anticoagulant such as heparin or EDTA
Whole blood contains all cellular and protein elements of blood
SERUM
Serum is the liquid obtained from whole blood after the blood is allowed to clot and the clot is removed
Serum does not contain cellular elements, fibrinogen or the other clotting factors from the blood
PLASMA
Plasma is the liquid supernatant obtained after centrifugation of non clotted blood that contains an anticoagulant
Plasma is the noncellular liquid fraction of the whole blood and contains all the proteins including albumin
PLASMA CONCENTRATION TIME CURVE •
ONSET TIME
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DURATION OF ACTION
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THERAPEUTIC WINDOW
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THERAPEUTIC INDEX
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PEAK PLASMA LEVEL
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TIME FOR PEAK PLASMA LEVEL AREA UNDER THE CURVE
PLASMA DRUG CONCENTRATION CURVES
THERAPEUTIC DRUG MONITORING
100
Response
) % ( y t i l i 50 b a b o r P
Toxicity
0
10
20
30
Drug Concentration (mg/L)
THERAPEUTIC CHANGES FOR COMMONLY USED DRUG DRUG
RANGE
Digoxin
0.5-2.0
ng/mL
Lidocaine
1.5-5.0
mg/L
Lithium
0.6-1.4
mEq/L
Phenobarbital
15-40
mg/L
Phenytoin
10-20
mg/L
Quinidine
2-5
Theophylline
5-15
mg/L mg/L
PROCESS FOR REACHING DECISIONS WITH THERAPEUTIC DRUG MONITORING A diagnosis is made A drug is selected
Dosage schedule is designed to reach a target plasma concentration A drug is administered Patient assessments are performed
Drug concentrations are determined
A pharmacokinetic model is applied
SAMPLE PLOTTING USING SEMILOG AND LINEAR GRAPHING PAPER •
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PLOT THE TIME VS. PLASMA DRUG LEVEL in page 24, 25 Label the points Use red ball pen for the line and label
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DRUG CONCENTRATIONS IN TISSUES (biopsy) URINE (rate and extent of systemic absorption) AND FECES (mass balance – entire dose given to the patient) SALIVA (pKa of the drug and pH of the saliva) •
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FORENSIC DRUG MEASUREMENTS (autopsy - abuse)
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Is the way in which the concentration of a drug or reactant in a chemical reaction affects the rate
Classes: • •
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Zero-order rate process First-order rate process Pseudo-order rate process
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Characterize the change of drug concentration in a particular reference region
Give the speed at which a drug: •
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Enters the compartment (absorption rate constant, ka) Distributes between a central and peripheral compartments (distribution rate constant) Is eliminated from the systemic circulation (elimination rate constant, k)
Zero versus First order elimination Zero-order
100%
80%
60%
90%
81%
40%
20%
First-order
100%
72%
64%
FIRST ORDER
ZERO ORDER
LINEAR SCALE •
It will have a curve line
SEMI LOG •
It will have a straight line
LINEAR SCALE It
will have a straight line
SEMI LOG It
will have a curve line
F I R S T O R D E R Z E R O O R D E R
Time after Drug Administration (hours
Amount of drug in the body (mg)
Amount of Drug eliminated Over preceding hour (mg)
Fraction of Drug Eliminated over preceding hour
0
1000
-
-
1
850
150
0.15
2
723
127
0.15
3
614
109
0.15
4
522
92
0.15
5
444
78
0.15
6
377
67
0.15
Amount of drug in the body (mg)
Amount of Drug eliminated
Fraction of Drug Eliminated over preceding hour
Time after Drug Administration (hours
Over preceding hour (mg)
0
1000
-
-
1
850
150
0.15
2
700
150
0.18
3
550
150
0.21
4
400
150
0.27
BASIC PHARMACOKINETICS AND PHARMACOKINETICS MODEL •
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MODEL – a hypothesis using mathematical terms to describe quantitative relationships concisely. PHARMACOKINETIC PARAMETER – is a constant for the drug that is estimated from the experimental data. (k depends on tissue sampling, timing of the sample, drug analysis and predictive model selected.
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INDEPENDENT VARIABLE – time
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DEPENDENT VARIABLE – drug concentration
Uses of pharmacokinetic models •
Predict plasma, tissue, and urine drug levels with any dosage regimen.
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Calculate the optimum dosage regimen for each patient individually.
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Estimate the possible accumulation of drugs and/or metabolites.
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Correlate drug concentrations with pharmacologic or toxicologic activity.
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Evaluate differences in rate or extend of availability between formulations (bioequivalence). Describe how changes in physiology or disease affect the absorption, distribution, or elimination of the drug. Explain drug interaction.
MODELS •
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EMPIRICAL MODELS – practically but not very useful in explaining the mechanism of actual process by which drug is absorbed. PHYSIOLOGICALLY BASED MODELS – sample tissue and monitor sample blood, biopsy, liver tissue. COMPARTMENT BASED MODELS – very simple and useful tool. Describe this situation is a tank containing a volume of fluid that is rapidly equilibrated with the drug.
DRUG CONCENTRATION •
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TISSUES URINE AND FECES SALIVA
DRUG CONCENTRATION •
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Drug concentrate in some tissues because of physical or chemical properties. Example include digoxin, which concentration in the myocardium Lipid soluble drugs (benzodiazepine), concentrate in the fats.
FACTORS CAUSING VARIABILITY IN PLASMA DRUG CONCENTRATION •
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Difference in individual’s ability to metabolize and eliminate the drug (genetics)
Variations in drug absorption Disease states or physiologic states (extremes of age) that alter drug absorption, distribution or elimination Drug interactions
DRUG CONCENTRATION •
The amount of drug in a given volume as mg/L;
Amount of drug Concentration of drug = Volume in which Drugs are distributed
TIME (hr)
Plasma drug level (ug/mL)
0
?
0.5
38.9
1
30.3
2
18.4
3
11.1
4
6.77
5
4.10
7
?
TWO PARAMETERS OF DRUG CONCENTRATION •
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The fluid volume of the tank that will dilute the drug The elimination rate of drug per unit of time.
MODEL 1 ONE-COMPARTMENT OPEN MODEL, IV INJECTION
1
K
MODEL 2 ONE-COMPARTMENT OPEN MODEL WITH FIRST-ORDER ABSORPTION
Ka
1
K
MODEL 3 TWO-COMPARTMENT OPEN MODEL, IV INJECTION K12
1 K
K21
2
MODEL 4 TWO-COMPARTMENT OPEN MODEL, WITH FIRST-ORDER ABSORPTION K12
Ka
1 K
K21
2
CATENARY CATENARY MODEL –MAMMILARY MODEL – strongly connected system, can estimate the amount in any compartment of the system
K12 Ka
K23
3
2
1 K21
K32
Model •
Is a mathematic description of a biologic system
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Is used to express quantitative relations concisely.
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A basic type of model used in pharmacokinetics is compartment models
Compartment •
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Is an entity which can be described d escribed by a definite volume and a concentration concentration Is a group of tissues with similar blood flow and drug affinity Is not a real physiologic or anatomic region Compartment models are deterministic because the observed drug concentrations concentrations determine the type of compartmental model required to describe the pharmacokinetics of the drug.
TYPICAL ORGAN GROUPS FOR CENTRAL AND PERIPHERAL COMPARTMENTS Central Compartment
Examples Peripheral Compartment
Heart Liver Lungs
Fat Tissue Muscle Tissue
Kidney Blood
Cerebrospinal Fluid
NOTE: Central compartment is also known as the highly blood-perfused compartment
Complex picture of drug interactions in the body. This gives an idea of the complexity of drug disposition. Shown are many of the steps to getting drug from one site in the body to another. Many of these processes are enzyme induced. Many of these processes
Significance of Compartment •
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Used to describe and interpret a set of data obtained by experimentation Used to characterize with reproducibility the behavior and the fate of a drug in biological system when given by a certain route of administration and in a particular dosage form Types • •
One-open compartment Multiple compartment •
Two-open compartment
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If the drug entering the body (input) distributes (equilibrates) instantly between the blood and other body fluids or tissues Drug is not necessarily confined to the circulatory system Drug may occupy the entire extracellular fluid, soft tissue or the entire body
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Distribution occurs instantly Is not pooled in a specific area Simpliest All body tissues and fluids are considered part of this compartment
Figure shows the body before and after a rapid I.V. bolus injection, considering the body to behave as a single compartment. In order to simplify the mathematics it is often possible to assume that a drug given by rapid intravenous injection, a bolus, is rapidly mixed. This represents the uniformly mixed drug very shortly after
ONE COMPARTMENT MODEL K
X0
X1
Where: X0 = Dose of the drug X1 = Amount of drug in body K = Elimination rate constant
Figure shows an intravenous bolus injection with a two compartment model. Often a one compartment model is not sufficient to represent the pharmacokinetics of a drug. A two compartment model often has wider application. Here we consider the body is a central compartment with rapid mixing and a peripheral compartment with slower distribution. The central compartment is uniformly mixed very shortly after drug administration, whereas it takes some time for the peripheral compartment to reach a pseudo equilibrium.
TWO-COMPARTMENT MODEL Where: X0 = Dose of the drug
X1 = Amount of drug in the
X1
X0
central compartment X2 = Amount of drug in the peripheral compartment K = Elimination rate constant of drug from the central compartment to the outside of the body K12 = Elimination rate constant of drug from the central compartment to the peripheral compartment K21 = Elimination rate constant of drug from the peripheral compartment to the central compartment
K12
K K21
X2
COMPARTMENT MODEL REPRESENTING TRANSFER OF DRUG FROM CENTRAL AND PERIPHERAL COMPARTMENTS
Intravenous Administration
Elimination
Central
PERIPHERAL
DRUG CONCENTRATION •
The amount of drug in a given volume as mg/L;
Amount of drug Concentration of drug = Volume in which Drugs are distributed
VOLUME OF (V) or (Vd) •
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Is an important indicator of the extent of drug distribution into the body fluids and tissue. V relates the amount of drug in the body (X) to the measured concentration in the plasma (C) V is the volume required to account for all the drug in the body if the concentrations in all tissues are the same as the plasma concentration.
X = VC
V=X C
C=X V Amount of drug
Volume of distribution = Concentration
LARGE vs. SMALL VOLUME OF DISTRIBUTION •
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A large volume of distribution usually indicates that the drug distributes Extensively into body tissues and fluids. Small volume of distribution often indicates limited drug distribution
USES OF VOLUME OF DISTRIBUTION •
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Indicates the extent of distribution but not the tissues or fluids in which the drug is distributing. Two drugs can have the same Vd but differ on the concentration site (muscles tissues, adipose tissues) The smallest volume in which a drug may distribute is the plasma volume/.
APPROXIMATE VOLUMES OF DISTRIBUTION COMMONLY USED DRUGS
DRUG
Volume of distribution
Nortriptyline
1300
Digoxin
440
Propranolol
270
Lidocaine
77
Phenytoin
45
Theophylline
35
Gentamicin
18
SAMPLE PROBLEMS •
•
If 100 mg of drug X is administered IV and the plasma concentration is determines to be 5 mg/L just after the dose is given. What is the volume of distribution? If the first 80-mg dose of Gentamicin is administered IV and results in a peak plasma concentration of 8 mg/L, What would be the volume of distribution?
TIME COURSE PLASMA GENTAMICIN CONCENTRATION
Concentration (mg/L)
Time after Dose (hours)
6
1
4.4
2
2.4
4
0.73
8
CLINICAL CORRELATE •
Drugs that have extensive distribution outside of the plasma appear to have a large volume of distribution.
Examples •
Chloroquine
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Digoxin
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Diltiazem
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Dirithromycin Imipramine Labetalol Metoprolol Meperidine Nortriptyline
PLASMA DRUG CONCENTRATION •
The prediction of plasma concentrations is based on known concentrations.
PLASMA DRUG CONCENTRATION CURVES
QUESTIONS: •
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If a 3 g of a drug are added and distributed through out a tank and the resulting concentration is 0.15 g/L, calculate the volume of the tank. A. 10 L E. 10 g/L B. 20 L F. 20 g/L C. 30 L G. 30 g/L D. 200 L H. 200 g/L
2. A drug follows a one-compartment model is given as an IV injection, and following plasma concentartions are determined at the times indicated Plasm lasma a Conc Concen enttrat ration ion (mg/L) g/L)
Time ime after ter Dose Dose (hours ours))
81
1
67
2
55
3
Using semilog graph paper pape r, determine the approximate concentration in plasma at 6 hours after the dose. A. 18 mg/L B. 30 mg/L g/L C. < 1 mg/L mg/L
BASIC PHARMACOKINETICS •
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To examine the concept of volume of distribution (V or Vd). One way is to compute apparent volume of distribution in the body. Apparent volume of distribution in the body is determined by measuring the plasma concentration immediately after administration before elimination has had a significant effect. The concentration just after IV administration (at time zero) is abbreviated as C0. The volume of distribution can be calculated using the equation: Amount of drug Xo (mg Vd = admi admini nist ster ered ed dose dose or Vd = -------------------Initial Drug Concentration Co (mg/L)
Measurement of Co •
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Co can be measured from direct measurement or estimation by back-extrapolation from concentrations determined at any time after the dose. It is done by extending to to the y-axis The point where that line crosses the y-axis gives an estimate of Co.
FLUID DISTRIBUTION IN ADULT The fluid portion (water) in an adult makes approximately 60% of the total body weight and is composed of: •
• •
35 % intracellular fluid 25 % extracellular fluid Plasma (4%) Interstitial fluid (21%)
• •
BLOOD –refers to the fluid portion in combination with formed elements (WBC, RBC and Platelets) PLASMA – refers only to the fluid portion of the blood (including soluble proteins but nor formed elements) SERUM – When the soluble protein fibrinogen is removed in the plasma
EXERCISE: •
A dose of 1000 mg of a drug is Plasma administered to a patient, and the Concentration following concentration results at the (mg/L) indicated times below. Assume a one100 compartment model. 67
Time after Dose (hours)
45
An estimate of the volume of distribution would be: A. 10.0 L. B. 22.2 L C. 6.7 L D. 5.0 L
2 4 6
EXERCISE Time after dose (hours)
Plasma Concentratiom (mg/L)
2
15
4
9.5
6
6
1. The plasma concentration at 9 hours after. 2. An estimate for the apparent volume of distribution of a 1000 mg dose
CLEARANCE •
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Clearance is a measure of a removal of drug from the body. Plasma drug concentrations are affected by the rate at which the drug is administered, the volume by which it distributes, and its clearance. A drug clearance and its volume of distribution determine its half-life. Clearance (expressed as volume/time) describes the removal of a drug from a volume of plasma in a given period of time (drug loss from the body)
CLEARANCE •
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Clearance does not indicate the amount of drug being removed. It indicates the volume of plasma (or blood) from which the drug completely removed, or cleared, in a given time period.
AREA UNDER THE CURVE •
The area under the plasma drug concentrationtime curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in mg*h/L.
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This area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered. The total amount of drug eliminated by the body may be assessed by adding up or integrating the amounts eliminated in each time interval, from time zero (time of the administration of the drug) to infinite time. This total amount corresponds to the fraction of the dose administered that reaches the systemic circulation.
AUC –AREA UNDER THE CURVE or area under the plasma concentration AREA METHOD •
AUC =
dose administered drug clearance
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Drug clearance = dose administered (X 0) AUC
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AUC = initial concentration (Co) elimination rate constant (K)
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AUC = (C1+C0)(t2-t1) + (C2+C1)(t3-t2) etc…… 2 2 AUC or terminal area = Clast K
AREA UNDER THE CURVE Computing the plasma concentration of 10 K = ln C last-lnC0 / t0 -tlast • •
get the Cp at time 0 and 10 hours, then compute for the K.
K = 0.2589 hr -1 ; Cp10 = 0.29 mg/L / 0.2589 hr -1 = 1.12 (mg/L) x hr Time after the dose (hours) 0 0.5 1.0 2.0 3.0 5.0 7.0 10.0 10.0
3.86
1.81 (mg/L) x hr
3.36
1.59 (mg/L) x hr
0.5
3.00
2.65 (mg/L) x hr
1
2.29
2.03 (mg/L) x hr
1.77
2.83 (mg/L) x hr
1.06
1.69 (mg/L) x hr
0.63
1.38 (mg/L) x hr
0.29
1.12 (mg/L) x hr
?
15.10 (mg/L) x hr
AUC0.5 AUC1 AUC2 AUC3 AUC5 AUC7 AUC10 = Clast K
•
Plasma Drug Concentration (mg/L) 0
2 3 5 7
TOTAL
The following drug concentration and time data were obtained after an IV bolus dose of procainamide (420 mg) Calculate the clearance by area method. Cl = X 0 / AUC
•
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(3.86 + 3.36) (0.5-0) 2 AUC0.5 AUC1 AUC2
0
•
1.81 (mg/L) x hr
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1.59 (mg/L) x hr
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2.65 (mg/L) x hr
•
0.5 1
2.03 (mg/L) x hr
AUC3
2
AUC5
3
AUC7
5
AUC10
7
2.83 (mg/L) x hr 1.69 (mg/L) x hr 1.38 (mg/L) x hr 1.12 (mg/L) x hr
•
•
AUC 0-t= 13.98 mg/L . hr AUC t- = Clast/K = = 0.29/0.2589 = 1.12 mg/L . hr AUC 0- = 13.98 mg/L.hr + 1.12 mg/L . hr = 15.10 mg/L . hr
Clearance •
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Drugs can be cleared from the body by many different mechanism, pathways, or organs, including hepatic biotransformation and renal and biliary excretion. Total body clearance of drug is the sum of all the clearances by various mechanisms.
CLEARANCE
Clt = Clr + Clm + Clb + Clother Where •
Clt = total body clearance (from all mechanisms, where t refers to total
•
Clrn = renal clearance (through renal excretion)
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Clm = clearance by liver metabolism or biotransformation
•
Clb = biliary clearance (through biliary excretion); and
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Clother = clearance by all other routes (gastrointestinal tract, pulmonary, etc.)
Model for Organ Clearance of a Drug •
•
For agent removed primarily by the kidneys, renal clearance (Clr) makes up most of the total body clearance. For drug primarily metabolized by the liver, hepatic clearance (Clm) is most important. Cin Q
Organ of Elimination (Liver, Kidney) Elimination (urine or bile)
Cout Q
•
•
•
•
Where Q (mL/min) is the blood flow through the organ Cin is the drug concentration in the blood entering the organ Cout is the drug concentration in the exiting blood. If the organ eliminations some of the drug, Cin is greater than Cout . Cin Q
Organ of Elimination (Liver, Kidney) Elimination (urine or bile)
Cout Q
E = extraction ratio •
We can measure an organ’s ability to remove a drug by relating Cin and Cout . This extraction ration is
E=
Cin – Cout Cin
Extraction Ratio (E)
Rating
>0.7
High
0.3-0.7
Intermediate
< 0.3
Low
EXTRACTION RATIO •
•
•
Must be fraction between zero and one. Organs that are efficient at eliminating a drug will have an extraction ratio approaching one Clearance of any organ is determined by blood flow and the extraction ratio.
Organ clearance = blood flow x extraction ratio or Clorgan = Q x Cin - Cout Cin
or Clorgan = QE
Example: •
• •
• •
• •
• • •
The amount of drug in the body is 850 mg and150 mg was eliminated via the bile. The blood flow is 20 mL/min. What would be the clearance in the bile? Cl bile = (850-150) / 850 = 0.82 x 20 mL/min = 16.40 mL/min The amount of drug in the body is 780 mg and 100 mg was eliminated via the lungs. The blood flow is 15 mL/min. What would be the clearance in the lungs? Cl lungs = (780-100) / 780 = 0.87 x 15 mL/min = 13.05 mL/min The amount of drug in the body is 670 mg and 130 mg was eliminated via the liver. The blood flow is 38 mL/min. What would be the clearance in the liver? Cl liver = (670-130) / 670 = 0.81 x 38 mL/min = 30.78 mL/min The amount of drug in the body is 550 mg and 160 mg was eliminated in the kidney. The blood flow is 46 mL/min. What would be the clearance in the kidney? (550-160) / 550 = 0.71 x 46 mL/min = 32.66 mL/min Compute for the total body clearance. C total = 16.40 + 13.05 + 30.78 + 32.66 = 92.89 mL/min
Effect of Clearance Extraction ratio (E)
Blood flow (Q) Clearance (Cl) (L/hour) (L/hour)
High (0.7-1.0)
Low
Low
Low (<0.3)
High
Low
High (0.7-1.0)
High
High
Low (<0.3)
Low
Low
