CLINICAL PHARMACOKINETI

CS

CLEARANCE (CL) describes the efficiency of

irreversible elimination of a drug from the body by
 excretion of unchanged drug.
 Metabolic conversion of the drug.
Clearance is defined as “the volume of blood cleared
of drug per unit time”

Clearance are additive

total clearance = (CL H) + (CL R )
 Why is CL important ?
Clearance determines the maintenance dose
rate (MD) required to achieve a desired serum drug
concentration (SDC) at steady state.
MD (mg/hr) = desired SDC (mg/L) x CL (L/hr)
or = Css X CL
 VOLUME OF DISTRIBUTION (Vd)

It is the parameter relating the

SDC to the total amount of the drug
in the body.
Vd (L) = Amt of drug in the body
(mg)/SDC (mg/L)
or = Dose/SDC0

How is Vd measured ?
 Why is Vd important ?

 Vd predicts the efficiency of

hemodialysis to remove the drug
from the body.

 Vd is used for calculating the

loading dose (LD).

LD (mg) = Vd (L) X desired SDC

(mg/L)
 HALF-LIFE (T1/2)

T1/2 is the time taken for the amount of drug in the body (o
r the SDC) to fall by half.
T1/2 (hr) = 0.693 X Vd/CL
 Why is half-life important ?

Half-life is a major determinant of :

 The duration of action after
a single dose.
 The time required to reach
steady state.
 The dosing frequency.
 BIOAVAILABILITY AND
FIRST PASS CLEARANCE
Absorption is the extent to which intact drug is absorbed
from the gut lumen into portal circulation.

Table 1
Determinants of drug absorption from the gut
A.Dissolution C.Intestinal motility
•Physico-chemical properties of drug •Dissolution of slowly soluble drugs (digoxin, sustained release
•Crystal size and form formulations)
•Excipients •Chemical degradation or metabolism by microflora
•Special dosage forms (sustained release, •Affected by : drugs (opiates, anticholinergics, metoclopramide);
enteric coated) disease states (gastroenteritis)
•pH (stomach and small intestine) D.Drug interactions in the gut lumen
B.Gastric emptying rate •Complexation (tetracyclines with divalent metal ions)
•Stability of drug at acid pH •Adsorption (anion exchange resins)
•Solution or solid dosage forms (liquids and small •Food interactions (many antibiotics)
particles empty more quickly) E.Passage through the gut wall
•Affected by: food; antacids; drugs (opiates, •Physico-chemical characteristics of the drug (quaternary
anticholinergics, metoclopramide); disease ammonium compounds)
(autonomic neuropathy) •Metabolism by enzymes in the intestinal endothelium
First pass clearance is the extent to which a drug is removed by the liver duri
ng its first passage in the portal blood through the liver to the systemic circulati
on.
 Why is first pass clearance
important ?
 Variability in drug response.  Alternative route of
 Relationship between oral administration.
and intravenous or parenteral  Drug interactions.
doses.  Liver disease.

Table 2
Effects of increase or decrease in hepatic drug metabolising enzyme activity on bioavailability
Hepatic enzyme % extracted Bioavailability
Activity first pass (% escaping first pass extraction)
A.Low extraction ratio drug
Normal 2 98
Doubled (induced) 4 96
Halved (inhibited) 1 99
B.High extraction ratio drug
Normal 90 10
Doubled (induced) 95 5
Halved (inhibited) 83 17
All the dose is assumed to be absorbed intact from the gut lumen. The low extraction ratio example is
characteristic of theophylline which has an intrinsic clearance (see previous article Aust Prescr 1990;
13:88 – 9) of about 15 mL/min. The high extraction ratio example is characteristic of verapamil which
has an intrinsic clearance of about 15 000 mL/min. Liver blood flow is normally around 1500 mL/min.
 Bioavailability is the fraction of the dose which reaches the
systemic circulation as intact drug. It depends both on how well th
e drug is absorbed and how much escapes being removed by the liv
er before reaching the systemic circulation.
 Absolute Bioavailability (F) is a measure of
bioavailability of a drug given by any routes against an
intravenous route.

F = AUC0/AUCi

If different doses are used, then

F = AUC0 x Dosei/AUCi X Dose0

Relative Bioavailability (f) is a measure of bioavailability
of one formulation against a second (reference) formulation
given by the same route.

f = AUCA/AUCB
 Bioequivalence is a clinical definition referring to
two formulations of a drug with similar extents and rates of
absorption that there is likely to be no clinically
important difference.
 Therapeutic Equivalence. If two formulations are
bioequivalence, they are usually as having therapeutic
equivalence provided that

 no impurity or pyrogen
 have the same amounts of stereoisomeric
active ingredients.
 Why is bioavailability i
mportant ?
Bioavailability is the major parameter that indicates how
much drug reach systemic circulation. Bioavailability study
is needed for drugs which have one or more of the following
characteristics :

1. Narrow therapeutic index : digoxin, theophylline,

antiepileptic drugs, antibiotics,
2. Lack of therapeutic effects is dangerous : digoxin,
antiepileptic drugs, antibiotics,
3. Poor absorption : digoxin, phenytoin, carbamazepine
4. Non-linear elimination kinetics : phenytoin
5. High first pass clearance : verapamil
 FDA approves the drug formulations that have
bioavailability in the range of 80-125% of the original
or innovator’s brand, this may not be appropriate in
certain situations, e.g.,

Case A. Changing from a formulation with bioavailability

of 80% to a formulation with 125% bioavailability.
Since F x MD = Css x CL
Css = F x MD/CL
If a formulation with 80% availability is used
Css1 = 0.8 x MD/CL
If switching to a formulation with 125% availability
Css2 = 1.25 x MD/CL
Css2/Css1 = 1.25/0.8 = 1.56
The SDC increases about 50% from initial levels
Case B. Changing from a formulation with bioavailability
of 125% to a formulation with 80% bioavailability.
Css2/Css1 = 0.8/1.25 = 0.64
The SDC decreases about 35% from initial levels

Consider the case of aminoglycosides, if patients switch

to formulations with very high bioavailability they may
suffer toxic effects at high peak and high trough levels.
 Predicting how drugs will
behave pharmacokinetically.
Drug A Drug B Drug C
Known parameters
Total clearance (L/hr) 80 3 7
Volume of distribution (L) 500 25 420
Fraction excreted unchanged 0.1 0.1 0.8
Liver blood flow (L/hr) 90 90 90
Predicted
Renal clearance (L/hr) (fraction 8
excreted unchanged X total Cl)
Hepatic clerance (L/hr) 72
Hepatic extraction ratio (hepatic Cl/liver blood flow) 0.8
Maximum oral bioavailability (%) 20
Affected by induction/inhibition of liver enzymes
when given orally Yes
Affected by liver blood flow when
given intravenously Yes
Decrease dose in liver disease Yes
Decrease dose in renal failure No
Half-life (hr) = 0.693 X Vd/Cl 4
Likely dosing schedule (times/day) 6
Time to reach steady state (hr) 20
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