This document provides an introduction to hepatic impairment studies. It discusses the role of the liver in pharmacokinetics including absorption, distribution, metabolism and excretion of drugs. Common liver diseases and their effects on pharmacokinetics are also described. The objectives and recommended designs of hepatic impairment studies are outlined, including categorization of impairment using the Child-Pugh score and dose adjustment recommendations based on area under the curve comparisons. Both single-dose and multiple-dose study designs are discussed.

1. INTRODUCTION OF
HEPATIC IMPAIRMENT
(HI) STUDY
Upendra Shukla

2. Antibiotics That Require Dose
Adjustment in Liver or Kidney
Disease
Kidney Disease Liver Disease
Cephalosporins (mostly 3rd gen) Most Cephalosporin
Clindamycin Aminoglycosides
Chloramphenicol Macrolides
Metronidazole Fluoroquinolones
Mafcillin Penicillins

3. Role of Liver on
Pharmacokinetics
 Absorption: especially for oral drugs
 Distribution: plasma protein binding, tissue binding and
lipid solubility
 Metabolism: conversion of pro-drugs into drugs (inactive to
active drug), conversion of active drug into inactive (for
excretion)
 Excretion: biotransformation for renal excretion and direct
excretion via gall bladder (colon)
 Kidney removes chemical from circulating
blood by filtration.
 Liver remove chemical by circulating blood
by metabolism.
 Even if they are excreted renally, they are
metabolized in the liver

4. Metabolism and Biotransformation
or Xenobiotics Metabolism
Metabolism
Hepatic Enzymatic
Extra
Hepatic
Enzymatic
Non-
enzymatic
 The liver transforms fat-
soluble metabolite/toxins into
a water-soluble form so they
can be released:
 Either through the kidneys
(elimination through the
urine)
 Or, into the bile (elimination
through the colon) This transformation
occurs during a two-
phase process:
 Phase I or oxidative phase
(by cytochrome P448 and
P450 systems)
 Phase II by conjugative
phase

5. Common Hepatic Diseases
Liver Disease
Acute
(common cause Hep
A, B, paracetamol
overdose)
Chronic
(common cause Hep
B, C, alcohol)
Cirrhosis
 Condition that results from
permanent damage or scarring of
the liver.
Alcoholic Cirrhosis
 If the liver is required to detoxify
alcohol continuously, liver cells may
be destroyed or altered resulting in
fat deposits (fatty liver) and more
seriously, either inflammation
(alcoholic hepatitis) and/or
permanent scarring (cirrhosis).
Viral hepatitis
 The most common forms world-
wide are hepatitis A, B and C.
Fatty Liver Obesity

6. Hepatic Impairment
 May alter absorption
 Alter metabolism (also
affect kidney function)
 Altered excretion
 Altered PK (which may alter
PD)
 This may lead to:
 drug accumulation (most
often)
 Change on safety, efficacy
and toxicity profile
 failure to form an active
metabolite (less often)

7. Why Hepatic Impairment Study is
Required?
Unpredictable: No
correlation of extent
of impairment Vs
amount of
accumulation (for an
individual drug)
No general rule can
be set for dosage
modification
To establish the
correlation of PK with
degree of hepatic
impairment, trial
should be conducted
The correlation is
assessed by
comparing the PK
of drug metabolite
in patients with
impairment with
matched controlled
healthy volunteers.
 Possible reasons of
unpredictability:
 No standardized method to
extent of impairment
 Extent of involvement of liver
 Type of liver disease
 Nature of drug

8. When to conduct HI Study?
 Conducted only after the SAD and MAD study is done
and complete PK profile in healthy volunteers is
established
 The timing of these trials is generally before or in
parallel with Phase II
 However sponsors prefer to conduct HI study after
Phase II study (after confirmation of efficacy
assessment in at-least one study)

9. Objective of HI Study
 To assess the influence of hepatic impairment on PK of drug and
metabolites
 To assess the influence of hepatic impairment on PD
 when co-response data is not available; or
 there is a concern that hepatic imp may alter PD response
 To assess the influence of hepatic impairment on safety and
tolerability of the study drug
 To allow recommendations for dose modifications
Yes
No

10. Development of Guidance on HI
Studies
ICH E7
Effect of liver
imp in elderly
patients
FDA 1999
Guidance on
hepatic imp
study
FDA 2003
Revised draft
guidance on
Hepatic imp
study
EMA 2005
Released
Guidance on
Hepatic imp
study

11. When HI Study Be Important?
HI study
Study
Recommended
hepatic
metabolism
and/or excretion
accounts for >20
% of the
absorbed drug
if its is a narrow
therapeutic range
drug
If the metabolism
of the drug is
unknown
 lithium and warfarin: drugs with
narrow TI
 Most antibiotics, beta-blockers and
aspirin: drugs with wider TI but >
20% hepatic involvement
 Vancomycin: No hepatic
involvement
 Gaseous or volatile drug: No

12. Categorization of Hepatic
Impairment
Laboratory criterion: like Bilirubin and Albumin,
Prothombine time
Clinical variables: like ascities or encephalopathy,
nutritional status, peripheral status and histological
evidence of fibrosis or combinations of variables
Child-Turcotte Score: proposed the scoring system by
using laboratory as well as clinical variables in 1964.
Primarily for alcoholic cirrhosis and portal hypertension
Child-Pugh Score: modified by Pugh et al in 1972. They
replaced criterion of nutritional status with the prothrombin
time or INR, and assigned scores of 1-3 to each variable.
 No single measure or group of measures has gained widespread clinical
use
 Total of 57 HI studies, conducted on 1995 to1998 were analyzed by USFDA
57HI Study
32Used Child-Pugh
25

13. Acceptable Classification of
Degree of Hepatic Impairment?
 Both FDA’s and EMA’s guidelines recommend use
of the Child-Pugh Score for categorization
 Originally used to predict mortality during surgery
 Also used to determine the prognosis, strength of
treatment and the necessity of liver
transplantation.

14. How to Calculate Child-Pugh
Score?
Score
1 2 3
Total Bilirubin (mg/dL)
Not PBC* <2.0 2.0 - 3.0 >3.0
Only for
PBC
<4.0 4.0 - 10.0 >10.0
Serum Albumin (g/dL) >3.5 2.8 - 3.5 <2.8
Ascites Absent Slight Moderate
Hepatic
Encephalopathy+
0 1 or 2 3 or 4
Prothrombin Time <4 4-6 >6
Grade Description Score
A Mild; well-compensated diseases 5-6
B Moderate; significant functional compromise 7-9
C Severe; decompensated disease 10-12
+Stages of Encephalopathy
 Stage 1: depression,
mild confusion
 Stage 2: Lethargy,
moderate confusion
 Stage 3: Marked
confusion, incoherent
speech, sleeping but
arousable
 Stage 4: Coma, initially
responsive to noxious
stimuli, but later
unresponsive
CPS=
2+3+2+2+1=10
Grade C, Severe

15. Recommended Design – Full
Study
Type of HI
Study Designs
Full study
design
Mild HI
Moderate HI
Severe HI
Matched
controlled
Reduced
study design
Population PK
approach
 Full study design is used:
 To develop dosing
recommendation across the
entire spectrum of hepatic
impairment
 Minimum 6 subjects in each
arms

16. FDA Analysis
57HI Study
32Used child-pugh
19Full Design
17Negative correlation
16Moderate category
1
2
13
25
Total of 57 HI studies,
conducted on 1995 to1998
were analyzed by USFDA

17. Recommended Design – Reduced
Study
Type of HI
Study
Designs
Full study
design
Reduced
study design
Moderate HI
Matched
Control
Population PK
approach
 Full study design is used:
 To develop dosing
recommendation for mild
and moderate spectrum
only
 Severe HI patients would
be contraindicated
 Finding in moderate
category would be applied
to mild group
 Population PK Approach:
 Assessment of hepatic
impairment by PK
Screening from Ph 2 and 3
studies
 Preplanned analysis of
effect of hepatic impairment
in phase trial
 Sufficient number of
patients with all sub-groups
should be included

18. Dose Adjustment
Recommendations
dose modification is
recommended
If, AUC of
Patients with
hepatic
impairment is
>2-fold of
AUC of
matched control

19. Single Dose or multi dose?
 Single-dose HI study - when the PK exhibit linear and time-
independence over the anticipated dose range
 A multiple-dose study - when the PK exhibit non-linear or time
dependence over the anticipated dose range
 In multiple dose study, PK assessment is appropriately carried out
at steady state