Download Effect of protein binding on PK/PD

Effect of protein binding on PK/PD
Clinical pharmacology weekly meeting
24 Feb. 2015
Sean Oosterholt
Protein Binding
• At therapeutic concentrations in
plasma, many drugs exist mainly
in bound form.
• The most important plasma protein in relation to
drug binding is albumin. Albumin binds many
acidic drugs and a smaller number of basic drugs
– Other plasma proteins include ß-globulin, a-acid
glycoprotein and Lipoproteins
Function of Protein Binding proteins
• Serum albumins are important in regulating blood volume
by maintaining the osmotic pressure of the blood
compartment
– They also serve as carriers for molecules of low water solubility this
way isolating their hydrophobic nature.
• ß-globulins are a subgroup of globulin proteins produced
by the liver or immune system
– Mostly involved with transport.
• α-acid glycoprotein is an alpha-globulin and act as a
carrier of basic and neutrally charged lipophilic compounds
•
The amount of a drug that is bound to protein depends on three factors:
–
–
–
•
the concentration of the drug
its affinity for the binding sites
the concentration of protein.
As an approximation, the binding reaction can be regarded as a simple association of
the drug molecules with a finite population of binding sites, analogous to drug–receptor
binding:
𝐷 + 𝑆
free
drug
•
Binding
site
⇌ 𝐷𝑆
complex
The usual concentration of albumin in plasma is about 0.6 mmol/l (4 g/100 mL).
With two sites per albumin molecule, the drug-binding capacity of plasma
albumin would therefore be about 1.2 mmol/L.
–
For most drugs, the total plasma concentration required for a clinical effect is much less than 1.2
mmol/l, so with usual therapeutic doses the binding sites are far from saturated, and the concentration
bound [DS] varies nearly in direct proportion to the free concentration [D].
– Under these conditions the fraction bound: [DS]/([D] + [DS]) is independent
of the drug concentration.
Some drugs, such as tolbutamide
work at plasma concentrations at
which the binding to protein is
approaching saturation
This means that adding more drug
to the plasma increases its free
concentration disproportionately.
•
Doubling the dose of such a
drug can therefore more than
double the free
(pharmacologically active)
concentration.
• It is the unbound drug that is pharmacologically
active
– Both in metabolism in the liver or any pharmacological
effect.
• The fraction of drug that is free in
aqueous solution can be less than
1%,
– small differences in protein binding
(e.g. 99.5 versus 99.0%) can have
large effects on free drug concentration
and drug effect.
– Differences are common between
human plasma and plasma from
species used in preclinical drug testing
Conditions in which the plasma
concentration of major plasma proteins are
altered
Conditions
Albumin
a-glycoprotein
Change in concentration
hepatic cirrhosis
+
burns
+
nephritic syndrome
+
pregnancy
+
myocardial infarcts
-
surgery
-
trauma
-
rheumatoid arthritis
-
Drug-drug interactions involving protein
binding
Before
Displacement
After
Displacement
% bound
95
90
% unbound
5
10
% bound
50
45
% unbound
50
55
% increase in
unbound fraction
Drug A
+100
Drug B
+10
Influence of drug binding on
pharmacokinetic parameters
Volume of Distribution:
• When concentrations are measured as “total plasma concentration” the
volume of distribution can become very small due to protein binding.
Example: Warfarin binds for 99% to plasma Albumin
• Plasma Concentrations after a 10mg Warfarin dose
– Total = 1 mg/L
– Bound = 0.99 mg/L
– Unbound = 0.01 mg/L
•
Apparent Volume
– Total = 10 mg/1 mg/L = 10 L
– Unbound = 10 mg/0.01 mg/L = 1000 L
Volume of distribution
• Small volumes of distribution
– Warfarin: 10L
– Gentamicin: 18L
• Low volume of distribution does not necessarily mean plasma
protein binding.
• Both Warfarin and Gentamicin have low volumes of distribution.
– Gentamicin is highly ionized and does not cross membranes very well.
– The volume of distribution of Gentamicin is close to the physical
volume of extracellular fluid.
Clearance
• Clearance is depends on the free drug
concentration and not on protein binding.
• However, only the free fraction of drug can be
cleared
𝑄𝑜𝑟𝑔𝑎𝑛 ∙ 𝑓𝑢 ∙ 𝐶𝑙𝑖𝑛𝑡
𝐶𝑙𝑜𝑟𝑔𝑎𝑛 =
𝑄𝑜𝑟𝑔𝑎𝑛 + 𝑓𝑢 ∙ 𝐶𝑙𝑖𝑛𝑡
Importance of protein binding
In most cases Clinically not very important
– Generally less than one third of the drug in the body in bound to plasma proteins even in
the most extreme cases.
•
A change in unbound fraction from 1% to 10% releases less than 5% of the total amount of drug
in the body, and produces at most a %5 increase in pharmacologically active unbound drug at the
site of action.
– Displacement of drugs from the binding site does not happen very often
•
Drugs that are “displacers” are few and rarely used therapeutically
Exception:
• IV bolus dose can cause rapid displacement of substances bound to plasma
proteins before redistribution happens
• Translating between species or from in vitro to in vivo
– Protein binding can have big differences between species
in vitro to in vivo
minimum inhibitory
concentration (MIC) is
the lowest concentration of
an antimicrobial that will
inhibit the visible growth of
a microorganism
Dashed line: Control growth
Filled squares: Drug without albumin
Filled circles: Drug with albumin
White squares: drug without albumin in a concentration equivalent to in vivo unbound
drug concentrations
Discussion
Plasma protein binding does not automatically result in
clearance restrictions.
• Example: Ciclesonide: bound for 99% to proteins but
clearance is close to hepatic blood flow
– Intrahepatic re-equilibration between bound and free drug
can occur so fast that the vast majority of drug can be
metabolized as the blood crosses the liver.
• Same could be said about the pharmacodynamic
effect, if association/dissociation is quick
Guidelines
• EMA:
– “The degree of protein binding of the investigational drug
should be determined before phase I. If the investigational
drug is extensively protein bound to a specific binding site
and present at concentrations saturating the binding sites,
the risk of displacement of other drugs known to be
subject to clinically relevant displacement interactions
could be evaluated in vitro at a time point relevant for the
clinical development program. If a clinically relevant
interaction is predicted based on in vitro data, an in vivo
study measuring unbound concentrations could be
considered.”