Transcript (mg/L) x CL

CLINICAL
PHARMACOKINETICS
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 ) + (CL )
H
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 (or 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
•Physico-chemical properties of drug
•Crystal size and form
•Excipients
•Special dosage forms (sustained release,
enteric coated)
•pH (stomach and small intestine)
B.Gastric emptying rate
•Stability of drug at acid pH
•Solution or solid dosage forms (liquids and small
particles empty more quickly)
•Affected by: food; antacids; drugs (opiates,
anticholinergics, metoclopramide); disease
(autonomic neuropathy)
C.Intestinal motility
•Dissolution of slowly soluble drugs (digoxin, sustained release
formulations)
•Chemical degradation or metabolism by microflora
•Affected by : drugs (opiates, anticholinergics, metoclopramide);
disease states (gastroenteritis)
D.Drug interactions in the gut lumen
•Complexation (tetracyclines with divalent metal ions)
•Adsorption (anion exchange resins)
•Food interactions (many antibiotics)
E.Passage through the gut wall
•Physico-chemical characteristics of the drug (quaternary
ammonium compounds)
•Metabolism by enzymes in the intestinal endothelium
First pass clearance is the extent to which a drug
is removed by the liver during its first passage in the portal
blood through the liver to the systemic circulation.
Why is first pass clearance
important ?
•Variability in drug response.
•Relationship between oral
and intravenous or parenteral
doses.
•Alternative route of
administration.
•Drug interactions.
•Liver disease.
Table 2
Effects of increase or decrease in hepatic drug metabolising enzyme activity on bioavailability
Hepatic enzyme
Activity
A.Low extraction ratio drug
Normal
Doubled (induced)
Halved (inhibited)
B.High extraction ratio drug
Normal
% extracted
first pass
2
4
1
Bioavailability
(% escaping first pass extraction)
98
96
99
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
the drug is absorbed and how much escapes being removed by the
liver 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
important ?
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)
Volume of distribution (L)
Fraction excreted unchanged
Liver blood flow (L/hr)
Predicted
80
500
0.1
90
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
3
25
0.1
90
7
420
0.8
90
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