Guidance for Industry
Pharmacokinetics in Patients with Impaired Hepatic Function:
Study Design, Data Analysis, and Impact on Dosing and Labeling
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind
FDA or the public. An alternative approach may be used if
such approach satisfies the requirements of the applicable
statutes and regulations. If you want to discuss an
alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the
appropriate FDA staff, call the appropriate number listed on
the title page of this guidance.
This guidance provides recommendations to
sponsors and applicants who plan to conduct studies to assess
the influence of hepatic impairment on the pharmacokinetics (PK)
and, where appropriate, the pharmacodynamics (PD) of a drug,
including therapeutic biological products. This guidance
discusses:
·
When studies should and should not be conducted
·
Recommended design and conduct of studies to
characterize the effects of impaired hepatic function on the PK
of a drug
·
Inclusion criteria for patient populations to be
studied
·
Analysis, interpretation, and reporting of the
results of the studies and description of the results in
labeling
The guidance does not consider ways to
assess the safety and efficacy of a drug to treat hepatic
disease or how to assess whether a drug causes hepatotoxicity.
FDA's guidance documents, including this
guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's
current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word should in
Agency guidances means that something is suggested or
recommended, but not required.
The liver is involved in the clearance of
many drugs through a variety of oxidative and conjugative
metabolic pathways and/or through biliary excretion of unchanged
drug or metabolites. Alterations of these excretory and
metabolic activities by hepatic impairment can lead to drug
accumulation or, less often, failure to form an active
metabolite.
Many reports in the biomedical literature
have documented that hepatic disease can alter the absorption
and disposition of drugs (PK) as well as their efficacy and
safety (PD). These reports have been based on studies in
patients with common hepatic diseases, such as alcoholic liver
disease and chronic infections with hepatitis viruses B and C,
and less common diseases, such as acute hepatitis D or E,
primary biliary cirrhosis, primary sclerosing cholangitis, and
alpha1-antitrypsin deficiency. Liver disease may
also alter kidney function, which can lead to
accumulation of a drug and its metabolites even when the liver
is not primarily responsible for elimination. Liver disease may
also alter PD effects (e.g., increased encephalopathy with
certain drugs in patients with hepatic failure). The specific
impact of any disease on hepatic function is often poorly
described and highly variable, particularly with regard to
effects on the PK and PD of a drug.
Measurements such as creatinine or
creatinine clearance have been used successfully to adjust
dosing regimens for drugs eliminated primarily by the kidneys.
Similar measures of hepatic function have been sought using
endogenous substances affected by the liver such
as bilirubin and albumin, or functional measures such as
prothrombin time, or the ability of the liver to
eliminate marker substrates such as antipyrine (Figg
et al., 1995), indocyanine green (ICG) (Figg et al., 1995),
monoethylglycine-xylidide (MEGX) (Testa et al., 1997), and
galactose (Tang and Hu 1992). Clinical variables have also been
studied. These include ascites or encephalopathy, nutritional
status, peripheral edema, and histologic evidence of fibrosis or
combinations of variables such as the Child‑Pugh classification
for alcoholic cirrhosis and portal hypertension (Zakim and Boyer
1996; Pugh et al., 1973), the Mayo risk scores for primary
biliary cirrhosis and primary sclerosing cholangitis (Dickson et
al., 1989; Wiesner et al., 1989), and the Maddrey-Carithers
discriminant function for acute alcoholic hepatitis (Maddrey et
al., 1978; Carithers et al., 1989) (see Appendix). Despite
extensive efforts, no single measure or group of measures has
gained widespread clinical use to allow estimation in a given
patient of how hepatic impairment will affect the PK and/or PD
of a drug.
Even though clinically useful measures of
hepatic function to predict drug PK and PD are not generally
available, clinical studies in patients with hepatic impairment,
usually performed during drug development, can provide
information that may help guide initial dosing in patients. This
information can be appropriately used with the understanding
that careful observation and dose titration are critical to
achieve the optimal dose in any given patient.
This guidance
recommends a PK study in patients with impaired hepatic function
if hepatic metabolism and/or excretion accounts for a
substantial portion (>20 percent of the absorbed drug) of the
elimination of a parent drug or active metabolite. The guidance
also recommends a hepatic impairment study even if the drug
and/or active metabolite is eliminated to a lesser extent (<20
percent), if its labeling or literature sources suggest that it
is a narrow therapeutic range drug.
If the metabolism of the drug is unknown and other information
is lacking to suggest that hepatic elimination routes are minor,
the Agency recommends that the drug be considered extensively
metabolized.
For some drugs,
hepatic functional impairment is not likely to alter PK
sufficiently to require dosage adjustment. In such cases, a
study to confirm the prediction is generally not important. The
following drug properties may support this conclusion:
·
The drug is excreted entirely via renal routes of
elimination with no involvement of the liver.
·
The drug is metabolized in the liver to a small
extent (<20 percent), and the therapeutic range of the drug is
wide, so that modest impairment of hepatic clearance will not
lead to toxicity of the drug directly or by increasing its
interaction with other drugs.
·
The drug is gaseous or volatile, and the drug and
its active metabolites are primarily eliminated via the lungs.
For drugs intended only for
single-dose administration, a hepatic impairment study will
generally not be useful, unless clinical concerns suggest
otherwise.
The following sections of the guidance
focus on a basic full study design (Section A), a
reduced study design (Section B), and a population PK
approach (Section C).
To develop
specific dosing recommendations across the entire spectrum of
hepatic impairment, a study should be carried out in patients in
the three Child-Pugh categories, mild, moderate and severe, as
well as controls. For this study design to provide evaluable
data, at least six subjects in each arm should be evaluated and
all other considerations set forth in section B should be taken
into account.
An FDA survey of
57 PK studies in patients with hepatic impairment in new drug
applications submitted between 1995 and 1998 revealed that 55
percent used the Child-Pugh scale to assess hepatic impairment.
Of the 57 studies surveyed, 19 estimated oral drug clearance in
normals and in patients in more than one Child-Pugh category
(i.e., mild, moderate, or severe). Of those 19 studies, 17
demonstrated a negative correlation (r2 between 0.5
to 1.0) between oral drug clearance and hepatic impairment, and
16 showed impaired hepatic metabolism in the patients in the
moderate Child-Pugh category.
Based on these
data, this guidance recommends that the Child-Pugh
classification be used to categorize the degree of hepatic
impairment in patients, just as serum creatinine or
creatinine clearance is used to categorize varying degrees of
renal impairment. In patients evaluated for this purpose, it is
important that impaired hepatic function — not some other
underlying disease — be the cause of alterations in the
Child-Pugh components (bilirubin, albumin, prothrombin,
encephalopathy and ascities). For example, in patients with
metastatic cancer, hypoalbuminemia, encephalopathy, and ascites
may be related to cancer cachexia or cancer metastatic to the
brain or peritoneal surfaces rather than impaired hepatic
function. Other approaches to assess varying degrees of hepatic
impairment may be appropriate, but a Child-Pugh categorization
should still be included for each patient.
Also, based on the
above data, a study design involving control subjects and
patients with a Child-Pugh category of moderate would generally
be appropriate. In that case, the findings in the moderate
category would be applied to patients with a mild Child-Pugh
category, and dosing in the severe category would generally be
contraindicated (see the Labeling section for details).
The primary
purpose of this guidance is to help sponsors and
applicants determine, based on the behavior of the drug in
patients with normal liver function, whether the PK and/or PD of
a drug and its active metabolites are altered in patients with
hepatic impairment to the extent that an adjustment to the
dosage would be indicated. For this reason, the control group
should be derived from the intended patient population (with
apparently normal hepatic function), not from young, healthy
volunteers. To the extent possible, the control group should be
similar to patients with respect to age, weight, and gender.
Depending on the drug, consideration is also recommended of
other factors with significant potential to affect the PK of a
drug to be studied (e.g., diet, smoking, alcohol intake,
concomitant medications, ethnicity). If concomitant medications
are used in the patients being studied, a careful assessment of
their influence on PK or PD should be made at the time of data
analysis. For drugs whose metabolism is mediated by enzymes
known to exhibit genetic polymorphism (e.g., CYP450, 2D6, or
2C19), the sponsor should take into consideration the
metabolic status of the enrolled subjects when analyzing the
results of the study. In addition to standard clinical
tests performed prior to entry, sponsors and applicants are
urged to perform assessments of hepatic blood flow and/or
intrinsic clearance using appropriate markers.
A sufficient
number of subjects should be enrolled in the study to provide
evaluable data from at least eight subjects in the control and
the moderate impairment arms.
A clinical study to investigate the
effects of hepatic impairment on drug disposition can be
designed, depending on circumstances, as a single-dose or
multiple-dose study with PK assessment of the parent drug and
any active metabolite(s). In a multiple-dose study, PK
assessment is appropriately carried out at steady state. A
single-dose study may be satisfactory for cases where prior
evidence indicates that multiple-dose PK is accurately predicted
by single-dose data for both parent drug and active
metabolites. This would be the case when the drug and active
metabolites exhibit linear and time-independent PK at the
concentrations anticipated in the patients to be studied. A
multiple-dose study is desirable when the drug or an active
metabolite is known to exhibit nonlinear or time-dependent PK.
Although the planned clinical dose is generally recommended as
the appropriate dose to be used in the study, a reduced dose may
be appropriate in patients with hepatic impairment if concern
exists about drug toxicity in patients with increased blood
levels. If more than one route of administration is proposed
for a drug, the study should use the route that provides the
maximum information regarding the impact of hepatic impairment
on the candidate drug’s elimination.
The blood sampling duration should
be adequate to determine the terminal half‑life of the drug and
its active metabolite(s), with the expectation that these times
may be extended in the patient compared to the control
population. For drugs that are highly extracted by the liver
(extraction ratio > 0.7) and that are extensively bound to
plasma proteins (fraction unbound < 10 percent), the Agency
recommends that the unbound fraction be determined at least at
trough and maximum plasma concentration. The clearance and
volume parameters are appropriately expressed in terms of both
unbound and total concentrations of drug in plasma/serum/blood.
To allow for analysis of the parent drug and its active
metabolite(s), analytical methods should exhibit sufficient
sensitivity and specificity. For drugs with stereochemical
properties, stereoselectivity in drug metabolism and protein
binding of enantiomers merit consideration (FDA 1992).
Population PK screening in phases 2
and 3 can be useful in assessing the impact of altered hepatic
function (as a co-variate) on PK if (1) these patients are not
excluded from phase 2 and 3 trials and (2) there is enough PK
information collected about patients to characterize them
reasonably well. If a population PK approach is used, patients
in phase 2 and 3 studies should be assessed for encephalopathy,
ascites, serum bilirubin, serum albumin, and prothrombin time
(components of the Child-Pugh score) or a similar group of
measures of hepatic function. A population PK study should
include the following features:
·
Preplanned analysis of the effect of hepatic
impairment
·
Appropriate evaluation of the severity of liver
disease
·
A sufficient number of patients and a sufficient
representation of the entire range of hepatic function to allow
the study to detect PK differences large enough to warrant
dosage adjustment
·
Measurement of unbound concentrations of the drug
when appropriate
·
Measurement of parent drug and active metabolite(s)
Such features are
important if the sponsor intends to use the results to support a
conclusion that no dosage adjustment is required for patients
with impaired hepatic function. Sponsors and applicants are
referred to the FDA guidance for industry Population
Pharmacokinetics (FDA 1999) for more detailed information
about the design and execution of population PK studies,
Pharmacodynamic
assessments may be useful in studies designed to assess the
effect of altered liver function, especially if
concentration-response data are not available or if there is a
concern that altered hepatic function may alter PD response.
The Agency recommends that the selection of PD endpoints be
discussed with appropriate FDA review staff and that they be
based on the pharmacologic characteristics of the drug and its
active metabolites.
The primary intent of the data analysis is
to assess the effect of hepatic impairment on the PK of the drug
and its active metabolites and, if possible, to relate a
specific measure of hepatic function or group of functions
(e.g., Child-Pugh) to a relevant PK measure or parameter such as
the area under the plasma concentration curve (AUC). From this
information, dosage recommendations for patients with impaired
hepatic function can be developed.
Plasma
concentration data (and urine concentration data, if collected)
should be analyzed to estimate measures or parameters describing
the PK of the drug and its active metabolite(s) (e.g., AUC, peak
concentration, (Cmax), apparent clearance (CL/F),
renal and nonrenal clearance (CLR and CLNR),
apparent volume of distribution (Vdz or Vdss),
terminal half-life (t1/2)). Where relevant, measures
or parameters can be expressed in terms of unbound
concentrations (e.g., apparent clearance relative to the unbound
drug concentration (Clu/F=Dose/AUCu, where the subscript “u”
indicates unbound drug)). Noncompartmental and/or compartmental
modeling approaches to parameter estimates can be employed.
In contrast to
approaches relating measures of renal impairment to drug
disposition, past experience indicates that it has been
difficult to develop a measure or group of measures of hepatic
function that predict alterations in drug PK. Nonetheless,
relationships between hepatic functional abnormalities (e.g.,
hepatic blood flow, serum albumin concentration, prothrombin
time, or overall impairment scores such as Child-Pugh), and
selected pharmacokinetic parameters (e.g., total body clearance,
oral clearance, apparent volume of distribution, unbound
clearance or dose-normalized area under the unbound
concentration-time curve) should be sought using linear and
nonlinear models. A regression approach for continuous
variables describing hepatic impairment and PK parameters is
appropriate, with the understanding that some correlations will
rely on categorical variables (e.g., Child-Pugh). Typically,
modeling results would include parameter estimates of the chosen
model and measures of their precision (standard errors or
confidence intervals). Prediction error estimates are also
desirable to assess appropriateness of the model.
The
principal objective of a hepatic impairment study is to develop
dosing recommendations so that patients and practitioners can
alter dose and dosing interval appropriately in the presence of
hepatic disease, again noting that subsequent careful titration
and observation are critical in this vulnerable population.
When applicable, it is also important to point out in dosing
recommendations that hepatic impairment does not
alter a drug’s PK. To reach this conclusion, a confidence
interval approach, rather than a significance test, is
preferred.
A general approach
in developing dosage recommendations is appropriately based on
the following considerations:
·
If the effect of hepatic impairment on the PK of
the drug is obvious (e.g., two-fold or greater increase in AUC),
dosage adjustments should be recommended in labeling. It should
be noted that for prodrugs (i.e., drugs with activity
predominantly due to hepatically generated metabolite), it is
possible that the dose would be increased, or the dosing
interval shortened, in hepatically impaired patients.
·
A conclusion that there is no effect
(really, no clinically important effect) of hepatic impairment
on the drug’s PK, would usually be supported by the
establishment of one of the following: (1) delineation of no
effect boundaries, prior to the conduct of the studies,
based on information available for the investigational drug
(e.g., dose- and/or concentration-response studies), or (2) in
the absence of other information to determine a different
equivalence interval, the employment of a standard 90 percent
confidence interval of 80-125 percent for AUC and Cmax.
FDA recognizes that documentation that a PK parameter remains
within an 80-125 percent no effect boundary would be very
difficult given the small numbers of subjects usually entered
into hepatic impairment studies. If a wider boundary can be
supported clinically, however, it may be possible to conclude
that there is no need for dose adjustment.
Labeling should reflect the data pertaining
to the effect of hepatic impairment on a PK and PD of a drug (if
known). Although the many permutations of intrinsic drug
characteristics and the effect of hepatic impairment on drug
performance preclude a simple specification of the labeling for
such drugs, in general drug dosage should be reduced in the
relevant population (Child-Pugh) for which significantly
impaired clearance is shown. Depending on the drug’s use and
therapeutic range, and the size of the effect on clearance, the
drug may be contraindicated in severe (Child-Pugh) hepatic
impairment or used with great caution. Conversely, if the
results show no significant impairment of drug clearance in the
moderate group, the drug can be administered in mild and
moderate hepatic impairment without any dose modification.
Labeling would generally indicate caution for severe hepatic
impairment if the drug has significant hepatic clearance, and if
there are no data to support a lesser labeling restriction.
If a study is not conducted for the
reasons listed in Section III.B, labeling should indicate that
the impact of hepatic impairment was not studied and that
effects requiring a dosage adjustment are unlikely for the
proposed drug. More detailed recommendations for labeling
statements are provided in the following sections.
Information in
this section of the labeling should include:
·
The mechanism of hepatic elimination (e.g., enzyme
pathways, glucuronidation, biliary excretion)
·
The percent of drug that is eliminated by these
mechanisms (e.g., metabolism, biliary excretion)
·
The disposition of active metabolites in patients
with impaired hepatic function, if applicable
·
The effects of hepatic impairment on protein
binding of parent drug and metabolites, if applicable
·
If applicable, a description of the effects of
impaired hepatic function on stereospecific disposition of
enantiomers of a racemic drug product if there is evidence of
differential stereoisomeric activity or toxicity
Based on studies performed in
accordance with recommendations in this guidance or an
acceptable alternative, information in this section of the
labeling should include:
·
A brief description of the pharmacokinetic changes
found in patients with hepatic impairment
·
Discussion of any issues of altered PD and dosing
adjustments required for patients with hepatic impairment
·
A reference to the WARNINGS/PRECAUTIONS,
CONTRAINDICATION and DOSAGE AND ADMINISTRATION sections.
The following text provides
examples of appropriate wording for this section of the
labeling.
a. If
studies show no effect of altered hepatic function
The simplest situation involves
drugs for which studies of impaired hepatic function have been
conducted and little or no effect on PK or PD was noted.
In a study comparing [X] patients
with moderate (as indicated by the Child-Pugh method) hepatic
impairment to [X] controls, the single/multiple dose PK/PD
disposition of ________ was not altered in patients with hepatic
impairment. No dosing adjustment is required in patients with
mild and moderate hepatic impairment.
b. If studies show an
effect of altered hepatic function
For drugs in
which PK or PD is influenced by hepatic impairment, the
following statement can be modified as appropriate and in
accordance with what is known about the drug (e.g., racemate
with different activity of stereoisomers, active or toxic
metabolite) and from the studies performed in accordance with
this guidance.
The disposition of ________ was
compared in patients with hepatic impairment and subjects with
normal hepatic function. Total body clearance of [unbound, if
applicable] _______/metabolite was reduced by ___% in patients
with moderate (as indicated by the Child-Pugh method) hepatic
impairment. The half‑life of _______/metabolite is prolonged by
____ in patients with moderate hepatic impairment. Protein
binding of ________/metabolite [is/is not] affected by impaired
hepatic function. The drug/metabolite accumulates to the extent
of ____ in patients with impaired hepatic function on chronic
administration. The dosage should be reduced in patients with
mild and moderate hepatic impairment receiving _______.
_______ should be [contraindicated/used with great caution] in
severe hepatic impairment (see WARNINGS/PRECAUTIONS,
CONTRAINDICATION and DOSAGE AND ADMINISTRATION).
c. If no studies of a
population with altered hepatic function exist
In cases where no
hepatically impaired patient population has been investigated,
as the basis for labeling claims, the following labeling
language is recommended:
Option 1: For
no hepatic contribution to the elimination of the compound
The influence of hepatic impairment
on the pharmacokinetics of______ has not been evaluated. Because
greater than 90% of the dose is excreted in the urine as
unchanged drug, hepatic impairment would not be expected to have
a significant effect on _______elimination.
Option 2: For
limited (<20 percent) hepatic elimination
Wide Therapeutic Range
The influence of hepatic impairment
on the pharmacokinetics of_____ has not been evaluated. Because
greater than 80% of the dose is excreted in the urine as
unchanged drug, hepatic impairment would not be expected to lead
to unsafe systemic exposure of ______.
Narrow Therapeutic Range
The influence of hepatic impairment
on the pharmacokinetics of_____ has not been evaluated. Because
the usual doses of the drug are close to doses that can cause
adverse effects, and there is in-vitro or in-vivo evidence of
hepatic contribution to the elimination of_____, hepatic
impairment could lead to an increased exposure and possibly an
increase in adverse effects. Patients with impaired liver
function may require reduced doses of ______or longer dosing
intervals. If ______ is used, close monitoring of patients with
impaired liver function is important (see WARNINGS/PRECAUTIONS,
CONTRAINDICATION and DOSAGE AND ADMINISTRATION).
Option 3: For
extensive (> 20 Percent) hepatic elimination
Wide Therapeutic Range
The influence of hepatic impairment
on the pharmacokinetics of____ has not been evaluated. Because
there is in-vitro or in-vivo evidence of extensive hepatic
contribution to the elimination of _____, hepatic impairment
would be expected to have significant effects on the
pharmacokinetics of _____. Caution should be exercised during
the use of ____ in this patient population. Patients with
impaired liver function may require reduced doses of _____ or
longer dosing intervals (see WARNINGS/PRECAUTIONS,
CONTRAINDICATION and DOSAGE AND ADMINISTRATION).
Narrow Therapeutic Range
The influence of hepatic impairment
on the pharmacokinetics of____ has not been evaluated. Because
there is in-vitro or in-vivo evidence of extensive hepatic
contribution to the elimination of _____, hepatic impairment
would be expected to have significant effects on
pharmacokinetics of _____. ____ should be avoided or used
with great caution in this patient population (see
WARNINGS/PRECAUTIONS, CONTRAINDICATION and DOSAGE AND
ADMINISTRATION).
Option 4: For
unknown hepatic elimination
In these circumstances, consider
the compound as extensively metabolized and use the above
format.
Use in Patients
with Impaired Hepatic Function: If the effects of hepatic
impairment result in clinically important changes in drug PK or
PD, this information should be included in the PRECAUTIONS
section of the labeling with reference to DOSAGE AND
ADMINISTRATION. If there is no information on the PK in
patients with impaired hepatic function, but the drug is known
to have a narrow therapeutic range, a statement in the
PRECAUTIONS, WARNINGS or CONTRAINDICATIONS sections of the
labeling should be included as appropriate.
As appropriate,
the following statements are recommended:
The influence of impaired hepatic
function on __________ pharmacokinetics or pharmacodynamics (if
known) is sufficiently small that no dosing adjustment is
required.
For cases in which impaired hepatic
function requires dosing adjustments, the appropriate
information should be included.
Special
consideration should be given to combination drug products. It
is reasonable to recommend dosing adjustment according to the
degree of hepatic impairment if there is sufficient information
to indicate that the pharmacokinetics of the individual
components are similarly affected by impaired hepatic function.
In situations for which this does not apply, the following
statement should be included:
Because the doses of this fixed
combination product cannot be individually titrated and impaired
hepatic function results in a reduced clearance of component A
to a much greater extent than component B, the combination
product should generally be avoided in patients with impaired
hepatic function (see WARNINGS or PRECAUTIONS, as appropriate).
In some cases,
where various ratios of the combination product are available,
it may be possible to direct physicians to a combination with
less of the hepatically cleared component.
Carithers RL, Herlong HF, Diehl AM, Shaw EW, Combes B, Fallon H,
Maddrey WC, Methyl-prednisolone therapy in patients with severe
alcoholic hepatitis, Ann Intern Med 1989; 110:685-90.
Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A,
Prognosis in primary biliary cirrhosis: model for decision
making, Hepatology 1989; 10:1-7.
FDA, Policy Statement for the
Development of New Stereoisomeric Drugs, May 1992.
FDA, Population Pharmacokinetics,
February 1999.
Figg WD, Dukes GE, Lesesne HR, Carson SW, Songer SS, Pritchard
JF, Hermann DJ, Powell JR, and Hak LJ, Comparison of
quantitative methods to assess hepatic function: Pugh’s
classification, indocyanine green, antipyrine, and
dextromethorphan, Pharmacother 15:693-700, 1995.
Maddrey WC, Boitnott JK, Bedine MS, Weber FLJr, Mezey E, White
RI, Corticosteroid therapy of alcoholic hepatitis,
Gastroenterology 1978; 75:193-9.
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R,
Transection of the oesophagus for bleeding oesophageal varices,
Brit J Surg 1973; 60:646-9.
Tang H-S, Hu OY-P, Assessment of liver function using a
novel galactose single point method, Digestion 1992;
52:222-31.
Testa R, Caglieris S, Risso D, et al., Monoethylglycinexylidide
formation measurement as a hepatic function test to assess
severity of chronic liver disease, Am J Gastroenterol
1997; 92:2268-73.
Wiesner RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL,
Hunter EB, et al., Primary sclerosing cholangitis: natural
history, prognostic factors and survival analysis,
Hepatology 1989; 10:430-6.
Zakim D and Boyer TD, Hepatology, A Textbook of Liver Disease,
W. B. Saunders Company, Philadelphia, 1996.
R
= 0.871 ln (B) + 2.53 ln (A) + 0.039 (Y) + 0.859 (E) + 2.38 ln
(PT).
[B=bilirubin,
mg/dL; A=albumin, g/dL; Y=age in years; E=edema; PT=prothrombin
time, sec]
Later the same year, another model was
developed for 174 patients with primary sclerosing cholangitis (PSC)
by Wiesner and colleagues at the same institution, but the
regression analysis identified blood hemoglobin (Hb, g/dL, below
12 g/dL), inflammatory bowel disease (IBD: 1 if yes, 0 if no), and
the histologic stage of hepatic fibrosis (S, 0 to 4) as important,
in addition to age and serum bilirubin (up to 10 mg/dL used if
observed value higher):
In contrast
to the flow dependent indocyanine green (ICG), antipyrine has a
low hepatic extraction ratio (2 percent) (Figg et al., 1995). It
is almost completely oxidized by various hepatic enzymes
(2-hydroxylation and 1-N-demethylation) and is limited by
metabolic capacity of the intrinsic enzyme activity and not
necessarily by hepatic blood flow or hepatic uptake. It has been
used extensively as a general marker for the functional ability of
the cytochrome P-450 oxidative pathway and is affected by a wide
range of liver diseases (e.g., chronic liver disease, hepatitis,
and cirrhosis). Antipyrine is effective in identifying moderate
and severe hepatic impairment, but its clearance does not change
in mild liver disease. Antipyrine clearance was found to
significantly correlate with Child-Pugh’s classification (r=0.67,
p=0.0003).
A widely used
marker of hepatic blood flow and hepatic uptake is ICG (Figg et
al., 1995). ICG is highly extracted by the liver (70-90 percent),
is not recovered in urine, is 95 percent bound to circulating
albumin, and is cleared by hepatic uptake, conjugation, and
excretion into the bile. Hepatic blood flow as assessed by
clearance of ICG is highly correlated with direct measurement
using electromagnetic flow meters. At standard doses, its
clearance follows first order kinetics. ICG clearance is reduced
in all forms of chronic liver disease. Elimination is
particularly impaired in alcoholic and biliary cirrhosis. The
percentage reduction found in patients with established cirrhosis
varies from 35-94 percent of that in healthy controls. ICG
clearance was found to correlate significantly with Child-Pugh’s
classification (r=0.86, p=0.0001).
This compound is the main metabolite of
lidocaine, produced by oxidative N-de-ethylation by the hepatic
CYP 3A enzyme system. It is measured at 15, 30, or 60 minutes
after an intravenous infusion over 2 minutes of 1 mg/kg of
lidocaine, and correlates well with Child-Pugh scores (Testa et al.,
1997).
A simplification (Tang and Hu 1992) of the
older, more tedious galactose elimination constant (GEC) developed
by Tygstrup in 1963 has been validated in patients with chronic
hepatitis and cirrhosis graded by the Child-Pugh scale and GEC.
The test is done by intravenously infusing 0.5 g/kg of galactose
and measuring serum galactose concentration enzymatically at 60
minutes later. Elevated blood galactose correlates sensitively
with hepatic dysfunction. There is some evidence that the GSP
test can be used to define clearance of both highly metabolized
drugs and drugs that are hepatically excreted but not metabolized.