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Hi,
We would like to perform a Pharmacokinetic study for a new drug in
patients with hepatic impairment.
Whether we can recruit subjects for the proposed indication?
Whether Child-Pugh classification alone is sufficient for recruiting
volunteers to detect hepatic impairment?
Our Drug is known to have high protein binding. In this case, what
additional parameters should be estimated to assess the pharmacokinetic
profile of the drug?
Narasimha Reddy
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Hi Narasimha
I don't know whether you can recruit this group of patients or not but a
"possible" alternative is using modelling and simulation, please see:
Strougo A, Yassen A, Krauwinkel W, Danhof M and Freijer J (2011) A
semi-physiological population model for prediction of the
pharmacokinetics of drugs under liver and renal disease conditions. Drug
Metabolism and Disposition 39:1278-1287.
Johnson TN, Boussery K, Rowland-Yeo K, Tucker GT and Rostami-Hodjegan A
(2010) A Semi-Mechanistic Model to Predict the Effects of Liver
Cirrhosis on Drug Clearance. Clinical Pharmacokinetics 49:189-206.
Edginton AN and Willmann S (2008) Physiology-Based Simulations of a
Pathological Condition: Prediction of Pharmacokinetics in Patients with
Liver Cirrhosis. Clinical Pharmacokinetics 47:743-752.
Apart from protein binding there are other system parameter changes that
should also be considered such as liver size and enzyme levels, organ
blood flows, renal function, etc. Of course the level of effect depends
on your drug properties.
Regards
Masoud
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The following message was posted to: PharmPK
Hi,
The Child-Pugh Classification still is the primary Classification on
which
authorities rely on, when assessing studies in hepatic impairment.
However,
Sponsors are encouraged (e.g. by the European Healthy Authority EMA) to
employ additional exogenous markers that have been used - and to some
extent
validated - to assess different aspects of hepatic impairment. Such
markers, tests include measures of metabolic hepatic capacity (e.g.
antipyrine, MEGX
(lidocaine metabolite, which is formed by CYP3A4), ICG (indocyanine
green ->
measure of liver blood flow) and galactose. Such markers may be used in
parallel with the Child-Pugh classification and a justification for the
choice of marker(s) should be given.
You may also consider to determine hepatic volume by ultrasound and/or
to
determine liver blood flow charactistics non-invasively by doppler
ultrasounds (redaouts may include HAPI = hepatic artery pulsatile index;
LVI
= liver vascular index; PVV = portal venous velocity).
The MEGX Test as well as the doppler ultrasound liver vascular indices
and
liver volume estimates has been employed in the following published
study:
Hermann R, Nassr N, Lahu G, et al. Steady-State Pharmacokinetics of
Roflumilast and Roflumilast N-Oxide in Patients with Mild and Moderate
Liver
Cirrhosis. Clin Pharmacokinet 2007; 46 (5): 403-416.
For further details you may also have a look in the respective EMA and
FDA
Guidance documents.
The selection of markers and asessemnts of course will depend on the PK
characteristics of your compound.
With kind regards,
Robert
Dr.med. Robert Hermann, FCP
Accredited Anaesthesiologist
Accredited Clinical Pharmacologist
Managing Director
Rossittenstrasse 15
D-78315 Radolfzell
Germany
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Dear Mr.Narasimha,
Q1. Whether we can recruit subjects for the proposed indication?
It may not be feasible to conduct the study in patients with the
condition for which the drug is indicated. An acceptable alternative is
to use volunteers with hepatic disease. It is acknowledged that
recruitment of suitable subjects may pose a difficulty. The most common
patient categories are subjects with viral hepatitis and alcoholic liver
disease. Subjects classified by the Child-Pugh system as having mild
impairment could have a normal hepatic function and for the majority of
drugs, clinically significant differences are more likely to be observed
in subjects with moderate and severe impairment. The sponsor should, as
far as possible, aim to include subjects in which altered
pharmacokinetics of the drug in question are likely to be detected.
Q2. Whether Child-Pugh classification alone is sufficient for recruiting
volunteers to detect hepatic impairment?
If the Child-Pugh classification is used, it must be assured that the
subjects included in the study have an adequate range of decrease in
serum albumin and increase in serum bilirubin and prothrombin time.
There are a number of systems that aim to categorise the severity of
hepatic impairment. Presently, no well-established, adequate markers for
hepatic function in terms of drug elimination capacity are available.
The Child-Pugh classification is the most widely used and is one way of
categorising hepatic function. However, it was not developed for the
purpose of predicting drug elimination capacity. Using this
classification, the subjects are grouped on the basis of two clinical
features (encephalopathy and ascites) and three laboratory-based
parameters (S-albumin, S-bilirubin and prothrombin time). Hepatic
dysfunction is categorised into groups called A, B and C or "Mild",
"Moderate" and "Severe" corresponding to 5-6, 7-9 and 10-15 scores,
respectively. As a result, even subjects with a normal hepatic function
are given a total score of 5 points (since each variable gives a score
of 1 point even within the normal range) and would consequently be
classified as having mild hepatic impairment. With regard to the
clinical chemistry parameters, i.e. S-albumin, S-bilirubin and
prothrombin time, none of these is specific for liver disease only.
In patients evaluated for classification purpose, it is important that
impaired hepatic function and not some other underlying disease is the
cause of alterations in the Child-Pugh components. When available,
biopsies can be used to confirm the diagnosis. Despite the limitations
mentioned above, the use of markers like serum albumin, prothrombin time
and bilirubin is encouraged and abnormalities in these parameters may be
better related to drug elimination capacity than other components of the
Child-Pugh classification, e.g. encephalopathy and ascites. If the
Child-Pugh classification is used, it must be assured that the subjects
included in the study have an adequate range of decrease in serum
albumin and increase in serum bilirubin and prothrombin time.
There are other Alternative approaches for categorizing Hepatic
impairment.
One way to ensure that the subjects to be studied actually have an
impaired metabolic capacity, would be to administer, for instance, a
CYP3A4 probe drug (if the drug under investigation is a CYP3A4
substrate) to the subjects to be included to observe if the
pharmacokinetics of the probe drug is altered (like a "positive control"
known to be specially sensitive to liver impairment). This probe would
have to be sensitive enough to identify a range of severity in hepatic
dysfunction. Exogenous markers that have been used to assess different
hepatic drug elimination mechanisms are antipyrine, MEGX (lidocaine
metabolite), ICG (indocyanine green) and galactose. Such markers may be
used in parallel with the Child-Pugh classification and a justification
for the choice of marker(s) should be given.
Q3. Our Drug is known to have high protein binding. In this case, what
additional parameters should be estimated to assess the pharmacokinetic
profile of the drug?
If the drug or metabolites exhibit a high extent of plasma protein
binding, the pharmacokinetics should be described and analysed with
respect to the unbound concentrations of the drug and active metabolites
in addition to total concentration.
Regards,
Dr.S.Gunasakaran, MD
Head - Clinical Research & Medical Affairs
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