26-11-2012, 05:41 PM
GUIDELINE ON THE EVALUATION OF THE PHARMACOKINETICS OF MEDICINAL PRODUCTS IN PATIENTS WITH IMPAIRED HEPATIC
FUNCTION
1PHARMACOKINETICS OF MEDICINAL.PDF (Size: 91.63 KB / Downloads: 172)
INTRODUCTION
Pharmacokinetic studies are used to identify special subgroups of patients in whom an
alternative dosing regimen may be indicated for efficacy and/or safety reasons. Since liver is an
important organ with respect to drug disposition, patients with hepatic impairment constitute
an important subgroup of such special populations.
Hepatic function decreases with age, but due to the high capacity of the liver this is considered
not to change the pharmacokinetics to a clinically relevant extent. Liver disease, however, is
known to be a common cause of altered pharmacokinetics of drugs. Hepatic function can be
decreased through different pathophysiological mechanisms. Worldwide, chronic infections
with hepatitis B or C are the most common causes of chronic liver disease, whereas in the
western world, chronic and excessive alcohol ingestion is one of the major causes of liver
disease. Other causes are uncommon diseases such as primary biliary cirrhosis, primary
sclerosing cholangitis and autoimmune chronic active hepatitis. Ongoing destruction of the
liver parenchyma in chronic liver diseases ultimately leads to liver cirrhosis and the
development of portal hypertension. However, even if liver cirrhosis is established, the residual
metabolic function of the liver may be rather well preserved for many years because of
regeneration of hepatocytes. Clinical symptoms related to hepato-cellular failure and portal
hypertensions are most importantly ascites, oesophageal varices and encephalopathy. Serum
markers of liver failure are low serum albumin and a prothrombin deficiency. Serum bilirubin as
well as other liver tests may or may not be affected to a varying degree, e.g. depending on the
liver disease (cholestatic versus hepatocellular). Liver cirrhosis is irreversible in nature, but
progression can be modified by e.g. abstinence of alcohol in alcohol liver cirrhosis.
STUDY DESIGN
The primary goal of a study in patients/subjects with impaired hepatic function is to identify
patients at risk in terms of severity of hepatic dysfunction. Depending on the extent to which
the pharmacokinetic parameters are affected, the next major objective is to determine the
extent to which the dosage should be adjusted to reduce the risk of under or over treatment in
these patients.
When designing a study, the normal pharmacokinetic properties of the drug should be the
starting point. Taking elimination characteristics into account, the sponsor should consider
which type(s) of hepatic conditions are likely to affect the pharmacokinetics and should focus
on including subjects with abnormalities in relevant markers.
Classification of hepatic impairment
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
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
(See Appendix). 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. Albumin is low due to decreased synthesis
by the hepatocytes in chronic liver disease but may also be influenced by inflammation and
increased synthesis of albumin has also been found in some patients despite low S-albumin
levels. Bilirubin may be increased due to cholestasis, hepatocellular failure or extrahepatic
causes such as hemolysis. The large reserve capacity for conjugation and excretion of bilirubin
in the liver as well as extrahepatic elimination makes bilirubin an insensitive marker of liver
failure. Prothrombin time is increased due to decreased hepatic synthesis of the coagulation
factors measured by the test, but is also influenced by e.g. vitamin K deficiency in cholestatic
liver disease. Prothrombin time may be decreased due to enzyme induction as in early stages of
cholestatic chronic liver disease. 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.
Alternative approaches
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.
Study population
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 (Section II.1). The type of hepatic disease in the study population should
depend on the pharmacokinetic characteristics of the drug under investigation.
A study design that includes only subjects with moderate impairment and healthy controls may
be used to screen for significant effects. If a significant effect is detected in the studied group,
the pharmacokinetics in subjects with milder and, if possible, more severe degrees of
impairment need to be evaluated to propose dose recommendations for these groups.
A within-study control group is recommended, and it should be comparable with the
hepatically impaired subjects with respect to age, gender, weight, genetic polymorphisms and
other factors with significant potential to alter the pharmacokinetics. Also factors like smoking
and alcoholic intake should be controlled for.. If a certain hepatic condition is especially
prevalent in the target population, this should be reflected in the choice of subjects in the study.
The use of historical controls instead of including a within-study control group with normal
liver function is discouraged since such designs may mask a difference in pharmacokinetics of
the drug.
Drug Administration
A single-dose study is sufficient when the drug and its active metabolites exhibit linear and
time-independent pharmacokinetics. A multiple-dose study is desirable when the drug or an
active metabolite is known to exhibit non-linear or time-dependent pharmacokinetics. If there
are indications that a reduction of the elimination capacity may result in dose-dependent
elimination of the drug, a multiple dose design is favourable.
In single-dose studies, if the drug has low first-pass exctraction, the same dose can in most
cases be administered to all subjects in the study, regardless of hepatic function. However, if
the drug shows a substantial first-pass effect due to extensive hepatic metabolism, a dose
reduction should be considered in the hepatically impaired group(s) for safety reasons.
For multiple-dose studies, lower or less frequent doses may be needed to prevent accumulation
of drug and/or metabolites to unsafe levels in subjects with reduced hepatic function. The
duration of dosing should in general be long enough to achieve a steady state. A loading dose
strategy may be suitable to facilitate this, particularly if the elimination half-life is significantly
prolonged in subjects with hepatic impairment.