PCOL2 Pharmacokinetics

8/8/2019 PCOL2 Pharmacokinetics

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Pharmacokinetics


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Absorption of Partially-Ionized

Drugs


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Aspirin pka = 3

Paracetamol pka = 9.5

Ibuprofen pka = 4.4


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Percent ionized

pka - pH If anion (weak acid) If cation (weak base)

- 4 99.99 0.01

- 3 99.94 0.06

- 2 99.01 0.99

- 1 90.91 9.09

- 0.9 88.81 11.19

- 0.8 86.30 13.70- 0.7 83.37 16.63

- 0.6 79.93 20.07

- 0.5 75.97 24.03


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Percent ionized


- 0.4 71.53 28.47

- 0.3 66.61 33.39

- 0.2 61.32 38.68

- 0.1 55.73 44.27

0 50.0 50.0

+ 0.1 44.27 55.73+ 0.2 38.68 61.32

+ 0.3 33.39 66.32

+ 0.4 28.47 66.61


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Percent ionized


+ 0.5 24.03 75.97

+ 0.6 20.07 79.93

+ 0.7 16.63 83.37

+ 0.8 13.70 86.30

+ 0.9 11.19 88.81

+ 1 9.09 90.91+ 2 0.99 99.01

+ 3 0.06 99.94

+ 4 0.01 99.99


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For acidic drugs, the lower the pka the

stronger the acid

Forbasic drugs the higher the pka thestronger the base


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The relation between ionization and pH is

sigmoidal


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pH-partition hypotheses

If the pH on one side of a cell membrane

differs from the pH on the other side of

the membrane, then:

1. The drug will ionize to different degrees

on respective sides of the membrane

2. The total drug conc. (ionized + non-

ionized) will be unequal on either sides of

the membrane


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pH-partition hypotheses

3. The compartment in which the drug is

more highly ionized will contain the

greater total drug conc.


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Goal

To deliver the right amount (dose) of drug

that is safe & effective at the right place

(target organ) and at the right time (onset

& duration of action).


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First-order and zero-order

kinetics


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Time of

collection (hrs)

Drug A (ug/mL) Drug B (ug/mL)

1 2000 2000

2 1500 1000

3 1000 500

4 500 250

5 0 125

6 0 63

7 0 31


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Which drug is eliminated by first-order

kinetics? Which one is zero-order kinetics?

Which one is concentration-dependentand which one is concentration-

independent?


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The rate of a chemical reaction or

pharmacokinetic process is the velocity

with which it occurs

The orderof a reaction is the way in which

the concentration of a drug in a chemical

reaction affects the rate


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Zero-order reaction

Drug conc. changes with respect to time at

a constant rate

dC/dt = -ko

C = -kot + Co

ko = zero-order rate constant

(conc./time)


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First-order reaction

Change in drug conc. with respect to time

equals the product rate constant and the

concentration of drug remaining

dC/dt = -kC

k = first-order rate constant

(reciprocal time)


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Integration yields:

C = Coe-kt

ln C = -kt + ln Co

log C = -kt/2.3 + log Co


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Biologic half-life (t1/2)

Time required for the concentration of a

drug to decrease by one half

Formula:

t =

Half-life is a constant and is related to the

first-order rate constant


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Biologic half-life (t1/2)

Unit: mins., sec., hrs.


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Elimination rate constant (k or kel)

Drug elimination is a first-order kinetic

process

Sum of the rate constants for removal ofthe drug from the body, including the rate

constants for renal excretion and

metabolism (biotransformation)


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Not affected by the route of administration

Affected by physiologic or pathologic

conditions of the patient (e.g. liver failure,age)


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Formula:

kel = ke + km

ke = rate constant for renal excretion; km =rate constant for metabolism

kel =

Unit: reciprocal time (sec-1, mins-1,

hrs.-1)


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Drug distribution

Reversible transfer of drug from one

location to another within the body

Most drugs do not distri

bute uniformlythroughout the body


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Apparent Volume of Distribution

(Vd)

Hypothetical volume ofbody fluid in

which the drug is dissolved

Not a true anatomic or physical volume

Is needed to estimate the amount of drug

in the body relative to concentration of

drug in the plasma

Measure of the apparent space in the

body available to contain the drug


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(Vd)

Can vastly exceed any physical volume

(since it is hypothetical) in the body

Reflects the volume necessary to containthe amount of drug homogenously at the

conc. found in the plasma, blood or water

(after giving a dose and getting the plasma

conc.)


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(Vd)

Formula:

Vd x Cp = Ab

Vd = apparent volume of distribution (L, mL)

Cp = plasma drug concentration (mg/mL,

ug/mL)

Ab = amount of drug in the body (mg, g)


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(Vd)

Reflects the amount of drug in the tissues,

not in the plasma

Inversely proportional in relation to thedrug plasma concentration

Unit: volume (mL, L)


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(Vd)

To calculate the Vd after intravenous bolus

injection

Vd =Ab

/Cp

Ab = dose of drug given by intravenous bolus (g,

mg)

Cp = extrapolated drug concentration at zero time onthe y-axis, after the drug equilibrates (ug/mL,

mg/mL)


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(Vd)

Influenced by:

1. binding affinity of a drug forblood ortissue elements

2. blood flow (i.e., delivery of drug to thetissues)

3. ability to cross biomembranes

4. physicochemical properties (lipophilicity,extent of ionization, pH, pka) thatdetermine partitioning to tissues


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Importance of Vd

Directly proportional to the half-life prolongs the half-life ___________

duration of action ??

Used for the computation of the loadingdose of a drug

Determine or predict the distribution of

drugs (is it predominantly in the plasma orin the body tissues?)

Compare the distribution characteristics of

various drugs


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(Vd)

A drug which is more bound to plasma

proteins than tissue proteins will ___ Cp

and ___ Vd

A drug which has a high affinity for

adipose tissues than plasma proteins will

___ Cp and ___ Vd

Vd of a lipophilic drug is large in an obese

patient


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Total body clearance (ClT, CL)

Measure of the ability of the body to

eliminate the drug


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Irreversible removal of drug from the body

by an organ of elimination

Units are flow

volume per time (mL/min,L/hr)

Defined as the volume ofblood irreversibly

cleared of drug per unit of time

Influenced by pathologic conditions and

age of the patient


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Product ofblood flow to the organ (Q) and

extraction ratio (ER) of that organ

CL organ = Q x ER Extraction ratio fraction of drug that is

irreversibly removed by an organ or tissue as

the plasma-containing drug perfuses that tissue


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Drug elimination rate divided by the

plasma concentration

ClT = rate of drug eliminationplasma concentration

= dDe/dt

CpdDe/dt = rate of drug elimination (mg/min, g/hr)

Cp = drug plasma conc. (mg/mL)


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According to the concept of clearance, the

body contains an apparent volume

distribution in which a drug is dissolved

(Vd) and a constant portion of this is

cleared or removed from the body per unit

time (kel or ke)

ClT =


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ClT = FDo

AUC

F= absolute bioavailability

Do = amount of drug administered (mg, g)

AUC = area under the curve, rate and extent of

drug absorbed in the systemic circulation

(mg.hr/mL)


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Sum of all clearances of the bodyCLT = CLR + CLNR

CLT = total body clearance

CLR = renal clearanceCLNR= non-renal clearance is often equated to

hepatic clearance (CLH)

It is always assumed that the drug iseliminated/cleared by first-order kinetics


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In relation to biologic half-life

ClT = keVd

ClT = 0.693Vdt 1/2

t = 0.693Vd

ClT


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Total body clearance (ClT, CL) is

influenced by:

Body surface area/ body weight

Cardiac output

Drug-drug interactions (renal or hepatic) Extraction ratio/ blood flow

Genetics

Plasma protein binding Hepatic and renal function


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Importance of ClT

Computation of the maintenance dose

Determine or predict the duration of action

of a drug

good orb

ad outcome


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Bioavailability

Measurement of the rate & extent

(amount) to which the active ingredient or

active moiety becomes available at the

site of action

Measure of the rate & extent of

therapeutically active drug that is

systemically absorbed


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For drugs not intended to be

absorbed in the bloodstream

Bioavailability may be assessed by

measurements intended to reflect the rate

& extent to which the active ingredient or

active moiety becomes available at the

site of action


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Pharmacokinetic studies in

determining bioavailability

Acute pharmacologic effect

Plasma drug concentration

Urinary drug excretion Comparative clinical trials

In vitro measurements ofbioequivalence

(e.g. dissolution testing)


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Acute pharmacologic effects

Changes in BP, heart rate, clotting time

Used if there is no assay for plasma drug

conc. is availab

le Used if the plasma conc.______________

to the pharmacologic response

Quantitation of pharmacologic effect

versus time profile can be used as a

measure


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Acute pharmacodynamic effect

Onset time

Intensity (proportional to what??)

Duration of action Therapeutic window


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Plasma drug concentration

tmax

Cmax

AUC


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Plasma-level time curve


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Urinary drug excretion

Is most accurate if the active therapeuticmoiety is __________________________

Assumed that a drug is eliminated by

______-order kinetics Cumulative amount of active drug

excreted in the urine (DU) - extent of

systemic drug ab

sorption Rate of drug excretion in the urine(dDU /dt)

rate of systemic drug absorption


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Urinary drug excretion

Time of the drug to be completely excreted

(t ) total time of the drug to be

systemically absorbed and completely

excreted after administration


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Correlating the plasma drug conc.

with cumulative drug excretion

C drug is completely eliminated, plasma

conc. approaches zero, max. amt. of drug

excreted in the urine

B max. rate of drug excretion, A & C

minimum rate of drug excretion

Proof: ClT = dDu/dt

Cp


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Correlating the plasma drug conc.

with cumulative drug excretion

Graph comparing rate of drug excretion

with plasma-level time curve of the same

drug appearance???


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Plasma data Urine data

t max t infinity

C max dDu/dt max

AUC Du at infinity


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Extent of drug bioavailability decreases

Plasma data Urine data Change

t max t infinity same

Cmax dDu/dt max

AUC Du at infinity


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Rate of drug bioavailability decreases

Plasma data Urine data Change

t max t infinity

Cmax dDu/dt max

AUC Du at infinity same


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Comparative clinical trials

Can be used to measure bioavailability

quantitatively

Highly v_________ and less precise than

other methods because of individual

differences in drug pharmacodynamics

and subjective measurements


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In vitro measurements

Rate of drug dissolution in vitro for certain

drug products correlate with drug

bioavailability in vivo (if it is stastically

adequate to be used as a predictor)


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Loading dose

Loading dose = Vd x Cp


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Maintenance dose

Intended to sustain a certain plasma conc.

(Ctarget)

Administered as a constant rate infusion

Ctarget = MD/Cl MD = R = Ctarget x Cl

MD = Ctarget x Cl x X


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Multiple doses

Drugs are given intermittently in a multiple-

dosage regimen for continuous or

prolonged therapeutic activity

Regimen is used to treat chronic diseases


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Multiple doses

If drug doses are given frequently before

the previous dose is completely eliminated

plasma drug conc. accumulate and

increase to a steady-state level


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Multiple doses


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Multiple doses

AUC of a dosing interval at steady state is

equal to AUC of a single dose of the drug

At steady state, plasma drug conc.

fluctuates between a maximum (Cmax) and

minimum (Cmin) value


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Multiple doses

When a multiple-dose regimen is

designed, only the dosing rate can be

adjusted easily


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Dosing rate

R = Dose

dosing interval

R = Do

X


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Dosing rate

Based on the size of the dose (Do) and

the interval between the doses (X) or the

frequency of dosing

As long as the dosing rate is the same, the

expected average drug conc. at steady

state (Cave) is the same


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Dosing rate

600 mg dose is given every 12 hour:

dosing rate 600 mg/12 hrs or 50 mg/hr

Dose: 300 mg every 6 hr or 200 mg every

4 hr also gives the same dosing rate (50

mg/hr) with the same expected Cave;

however, the Cmax and Cmin values will bedifferent


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Dosing rate

For a larger dose given over a longer

interval (e.g. 600 mg every 12 hr), the Cmaxis higher and the Cmin lower compared with

a smaller dose given more frequently (e.g.200 mg every 4 hr)

PCOL2 Pharmacokinetics

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