Clinical PharmacokineticsClinical PharmacokineticsClinical PharmacokineticsClinical Pharmacokinetics

Fundamental hypothesis: a relationship exists between the pharmacological or toxic response to a drug and the accessible concentration of the drug (e.g., in blood).

Volume of distribution (Vd) Clearance (CL) Bioavailability (F) Half life

Volume of DistributionVolume of DistributionVolume of DistributionVolume of DistributionVolume of distribution (Vd) relates the amount of drug in the body to the plasma concentration of drug (C).

**The apparent volume of distribution is a calculated space and does not always conform to any actual anatomic space.**

note: Vd is the fluid volume the drug would have to be distributed in if Cp were representative of the drug concentration throughout the body.

)/(

)()(

LgC

gbodyindrugofAmountLVd

Drug Vd(L/70 kg body)

Chlroquine 13000

Warfarine 9.8

Clearance (CL)Clearance (CL)Clearance (CL)Clearance (CL)

Clearance is the most important property to consider when a rational regimen for long-term drug administration is designed.

The clinician usually wants to maintain steady-state drug concentrations known to be within the therapeutic range.

)/(

)/(neliminatioofRate)/(

LgC

hghLCL

Clearance of most drugs is constant over a range of

concentrations.

This means that elimination is not saturated and its

rate is directly proportional to the drug concentration:

this is a description of 1st-order elimination.

)/(min)/()/(neliminatio LgCLClhgofRate

First order elimination

0

100

200

300

400

500

0 100 200 300

Time (min)

Pla

sma

Con

cent

ratio

n(C

p)

Capacity limited elimination(zero order) Phenytoin, Ethanol and Aspirin

CK

vCL

m

m

CK

CVneliminatioofRate

m

max

CCLneliminatioofRate

Zero order elimination

0

50

100

150

200

250

300

0 20 40 60 80 100

Time(min)

Pla

sma

conc

entr

aion

(Cp)

Flow dependent elimination

Alprenolol Lidocaine

Amitriptyline Meperidine

Morphine Imipramine

Propranolol Isonizide

Verapamil Labetalol

CL in a given organ may be defined in terms of blood flow and [drug].

Q = blood flow to organ (volume/min)

CA = arterial drug conc. (mass/volume)

CV = venous drug conc.

rate of elimination = (Q x CA) - (Q x CV) = Q (CA-CV)

Extraction RatioExtraction RatioExtraction RatioExtraction Ratio

Division of the previous equation by the concentration of drug that enters the given organ of elimination yields an expression for clearance of the drug by the organ:

CLorgan = Q(CA-CV/CA) = Q x E

E is referred to as the extraction ratio

CCLneliminatioofRate

Rate of elimination = (Q x CA) - (Q x CV) = Q (CA-CV)

Half Life

Half life is the time required to change the plasma concentration to one-half or twice of its original value

CL

Vt d

693.0

2/1

Half Life

Half-life is the time taken for the concentration of drug in blood to fall by a half

0

10

20

30

40

50

60

70

80

90

100

110

0 1 2 3 4 5 6 7 8 9

Time (hours)

Co

nce

ntr

atio

n (

mg

/L)

Time to Steady State Time to steady state depends on half life

Half life DOES NOT depend on: Dose Dosage Interval

Tss = 4 x t½

Time to drug accumulation and elimination

)1( ktss eCC

2/1

)2ln(

tk

ktss eCC

)1( 2/1

2lnt

tSS eCC

Effect of half life on plasma concentration at the beginning of dosing

0

20

40

60

80

100

120

0 1 x 2 x 3 x 4 x 5 x

Number of half lives

Pla

sma

conc

(m

g/l)

Plasma conc

Effect of half life on plasma concentration at the end of dosing

0

5

10

15

20

25

0 x 1 x 2 x 3 x 4 x 5 x

No of half lives

Pla

sma

conc

(m

g/l)

Plasma conc

How do you change the plasma concentration?

To change the plasma concentration: Change the dose Change the dosage interval

Bioavailability

The fraction of unchanged drug reaching the systemic circulation following administration by any route.

IV

route

AUC

AUCFiltyBioavailib )(

The target concentration approaches to designing a rational dosage regimen

Maintenace Dose

Dosing ratess = Rate of eliminationss

Dosing ratess = CL X TCIf the bioavailability is less than 100 percent then

oralss F

rateDosingrateDosing

And if we want to give the drug intermittently:

Maintenace Dose = Dosing rate x Dosing interval

Loading Dose

Loading dose = Vd X TC

While the estimation of the amount of a loading dose may be quite correct, the rate of administration can be crucial in preventing excessive drug concentration, and slow administration of an intravenous drug (over minutes rather than seconds) is almost prudent practice

Good Luck