5 Quantitive Pharmacokinetics

Question 1

concentration =

Answer 1

mass/ volume

Question 2

Volume of Distribution, VD

Answer 2

Used to estimate dose required to result in a certain [drug] in plasma

Question 3

Volume of Distribution, VD

Answer 3

VD is the (apparent) volume of distribution.
The volume of plasma that would be required to contain the drug dose at the concentration measured in plasma.
Can be greater than total volume of a human due to tissue binding ! eg VD for amiodarone = 7000 L
Units: either L or can be expressed as L/Kg (to correct for different size patients)

Question 4

Dose =

Answer 4

C VD

Question 5

K is..

Answer 5

the elimination rate constant

Question 6

Cl

Answer 6

clearance - the volume of plasma cleared of drug per unit time

Question 7

Ca > Cv or Ca < Cv

Answer 7

The concentration of the drug in the blood leaving the liver will be lower

Ca > Cv

Question 8

Amount of drug entering/minute =

Answer 8

QCa

Question 9

Amount of drug leaving/minute =

Answer 9

QCv

Question 10

Extraction ratio =

Answer 10

E = Ca-Cv/ Ca

E = 1 all eliminated 
E= 0 none eliminated

Question 11

What is the extraction ratio

Answer 11

The extraction ratio is the fraction of drug entering a tissue that is eliminated

Question 12

Rate of elimination =

Answer 12

blood flow rate x fraction of blood cleared of drug blood x Conc of drug in blood
Cl x C

Question 13

Volume of distribution is..

Answer 13

volume that it appears the drug is dissolved in

Question 14

Clearance varies with..

Answer 14

age and disease

Question 15

Dose =

Answer 15

Cl x AUC∞

By measuring AUC∞ we can calculate Cl

Question 16

Half life, t1⁄2

Answer 16

The time required for elimination of half of the absorbed drug

Question 17

First order

Answer 17

– The Rate is proportional to “one variable” (hence “first”) – Here Rate depends on [Drug]
Rate α [Drug]
Rate = k [Drug]

(if [Drug] doubles, so does the rate)

Question 18

Zero order

Answer 18

– The rate is constant
– It depends on “zero variables” (hence “Zero order”)

Rate is constant and doesn’t change with [Drug]

Rate = k
(if [Drug] doubles, rate stays the same)

Question 19

First order drug elimination following intravenous bolus administration

Answer 19

C=C0e-kt

C0 = concentration of drug in plasma at t=0 (immediately after administration) 
k = elimination rate constant, fraction of drug eliminated per minute
k = 0.1 min-1  10% of drug is eliminated per minute

Question 20

k =

Answer 20

• slope x 2.303

Question 21

kt1⁄2 =

Answer 21

ln2

Question 22

VD =

Answer 22

Dose/ C0

Question 23

ASSUMING: first order conditions, no non-linear PK, fast absorption and distribution
• Doubling the dose..

Answer 23

extends exposure above a certain concentration by t1⁄2

Question 24

Relationship of Clearance and elimination rate constant

Answer 24

• k = elimination rate constant,
• k = fraction of drug eliminated per minute

k = Cl/ VD

K is the fraction of the drug thats eliminated per min

Question 25

larger volume of distribution results in..

Answer 25

slower elimination

Question 26

Half life depends on..

Answer 26

clearance and volume distribution

Question 27

t1/2 =

Answer 27

0.693 x VD / Clearance

Question 28

Effects on Volume of Distribution - Ageing - Obesity - Pathologic fluid How do these effect half-life

Answer 28

Aging (decreased muscle mass → decreased distribution) Decreased Obesity (increased adipose mass → increased distribution) Increased ``` Pathologic fluid (increased distribution) increased ```

Question 29

Effects on Clearance - Cytochrome P450 induction - Cytochrome P450 inhibition - Cardiac failure - Hepatic failure - Renal failure How do these effect half-life

Answer 29

Cytochrome P450 induction (increased metabolism) Decreased Cytochrome P450 inhibition (decreased metabolism) Increased ``` Cardiac failure (decreased clearance) Increased ``` ``` Hepatic failure (decreased clearance) Increased ``` ``` Renal failure (decreased clearance) Increased ```

Question 30

Intravenous Infusion

Answer 30

``` • Drug delivered over minutes-hours – allows precise and controlled exposure – adjust concentration – stop if required – short infusion sometimes used to reduce Cmax and adverse events following rapid bolus injection ```

Question 31

Intravenous Infusion | • Drug concentration increases..

Answer 31

• Drug concentration increases to a plateau value Css – rate of elimination = rate of infusion C = Css(1-e-kt)

Question 32

Intravenous Infusion | Calculation of infusion rate

Answer 32

•At plateau (“steady state concentration): Rate of elimination = Rate of infusion •Rate elimination = Cl x Css k = Cl VD •so if we know Cl and the Css we wish to achieve we can calculate the required infusion rate •Required rate of infusion Rinf = Cl x Css

Question 33

Intravenous Infusion | Loading Dose

Answer 33

* Useful to quickly reach Css * bolus iv dose * Loading dose = CssVD

Question 34

Intravenous Infusion | the longer the half life..

Answer 34

the longer it will take to get to the steady state

Question 35

Intravenous Infusion | - Plateau concentration determined by..

Answer 35

1. Plateau concentration determined by infusion rate and clearance Rinf = Cl x Css Css = Rinf/Cl Increasing the infusion rate will increase the final Css

Question 36

Intravenous Infusion | - Time to reach plateau depends on..

Answer 36

2. Time to reach plateau depends on the elimination constant (or t1/2). Increasing the infusion rate will NOT REDUCE the time to reach Css because Css will be increased.

Question 37

• Linear pharmacokinetics

Answer 37

– pharmacokinetic parameters don’t change with dose | – increasing dose increases exposure (AUC Css etc) proportionately

Question 38

• Non-linear pharmacokinetics

Answer 38

– Pharmacokinetic parameters change with dose of drug – increasing dose has a disproportionate effect on exposure » eg exposure may be higher than expected because a metabolising enzyme is saturated » eg exposure may be lower than expected because VD increases (eg drug accumulates in a different compartment at higher dose)

Question 39

Rate of increase of drug in body =

Answer 39

Rate of absorption - Rate of elimination

Question 40

Effect of dose & absorption rate on concentration profile Increased dose results in

Answer 40

– increased Cmax and AUC | – no effect on Tmax

Question 41

Effect of dose & absorption rate on concentration profile Changing absorption kinetics results in

Answer 41

– eg different formulation, p.o. admin with food | – Cmax and Tmax altered

Question 42

Effect of dose & absorption rate on concentration profile Absorption can become..

Answer 42

rate-limiting – usually elimination (disposition) is rate limiting – but in some cases absorption is so slow that this becomes limiting: » declining phase represents decrease absorption and elimination » elimination rate = absorption rate

Question 43

kel =

Answer 43

Clearance / VD independent of dose

Question 44

Bioavailability , F

Answer 44

• i.v. administration – all of the dose is bioavailable – F=1 (sometimes expressed as F=100% ) • Non i.v. – some drug may not reach systemic circulation – incomplete absorption » insufficient time, poor dissolution, poor permeability – metabolism before absorption » eg p.o. : gut flora, enzymes in gut wall, first pass metabolism – F<1 • amount reaching systemic circulation = F x Dose

Question 45

How can we measure bioavailability, F ?

Answer 45

Fpo = | Doseiv AUCpo/ Dosepo AUCiv

Question 46

Repeated doses

Answer 46

2nd dose of drug is given before the 1st one has been eliminated. Thats why 2nd dose is higher

Question 47

Repeated dose equation | dose =

Answer 47

Dose = t Cl Css,av/ F

Question 48

Css,av depends on..

Answer 48

dose & frequency

Question 49

Loading Dose

Answer 49

– an initial “high” dose of drug to quickly plasma drug concentration to the desired level – particularly important for drugs with large VD Doseloading = VD Css/ F

Question 50

Maintenance dose

Answer 50

– once desired plasma drug concentration is achieved, them maintenance dose compensates for drug elimination Dosemaintenance = t Cl Css, av/ F