Effects of Liver disease on Pharmacokinetics

1. EFFECT OF HEPATIC DISEASE
ON PHARMACOKINETICS

2. • Hepatic disease can alter drug pharmacokinetics and pharmacodynamics.
• Hepatic disease may include common hepatic diseases, such as
• alcoholic liver disease (cirrhosis) 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
• a1-antitrypsin deficiency
• In addition, drug-induced hepatotoxicity is the leading cause of acute liver failure in
the United States (Chang and Schiano, 2007).

3. • Drugs are often metabolized by one or more enzymes located in cellular membranes in
different parts of the liver.
• Drugs and metabolites may also be excreted by biliary secretion.
•
• Hepatic disease may lead to
• drug accumulation,
• failure to form an active or inactive metabolite,
• increased bioavailability after oral administration,
• and other effects including possible alteration in drug–protein binding.
• 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.

4. • The major difficulty in estimating hepatic clearance in patients with hepatic
disease is the complexity and stratification of the liver enzyme systems.
• In contrast, creatinine clearance has been used successfully to measure
kidney function and renal clearance of drugs.
• Clinical laboratory tests measure only a limited number of liver functions.
• Some clinical laboratory tests, such as the aspartate aminotransferase
(AST) and alanine aminotransferases (ALT), are common serum enzyme
tests that detect liver cell damage rather than liver function.

5. • Other laboratory tests, such as serum bilirubin, are used to measure
biliary obstruction or interference with bile flow.
• Presently, no single test accurately assesses the total liver function.
• Usually, a series of clinical laboratory tests are used in clinical practice
to detect the presence of liver disease, distinguish among different
types of liver disorders, gauge the extent of known liver damage, and
follow the response to treatment.

6. • A few tests have been used to relate the severity of hepatic impairment to
predicted changes in the pharmacokinetic profile of a drug (FDA Guidance
for Industry, 2003).
• Examples of these tests include the ability of the liver to eliminate marker
drugs such as antipyrine, indocyanine green, monoethylglycine-xylidide,
and galactose.
• Furthermore, endogenous substrates, such as albumin or bilirubin, or a
functional measure, such as prothrombin time, has been used for the
evaluation of liver impairment.

7. Dosage Considerations in Hepatic Disease
• Several physiologic and pharmacokinetic factors are relevant in considering
dosage of a drug in patients with hepatic disease (Table 24-10).
• Chronic disease or tissue injury may change the accessibility of some enzymes as
a result of redirection or detour of hepatic blood circulation.
• Liver disease affects the quantitative and qualitative synthesis of albumin,
globulins, and other circulating plasma proteins that subsequently affect plasma
drug protein binding and distribution.
• As mentioned, most liver function tests indicate only that the liver has been
damaged; they do not assess the function of the cytochrome P-450 enzymes or
intrinsic clearance by the liver.

9. • Because there is no readily available measure of hepatic function that
can be applied to calculate appropriate doses, enzyme-dependent
drugs are usually given to patients with hepatic failure in half-doses,
or less.
• Response or plasma levels then must be monitored.
• Drugs with flow-dependent clearance are avoided if possible in
patients with liver failure.

10. Fraction of Drug Metabolized
• Drug elimination in the body may be divided into
• (1) fraction of drug excretion unchanged, fe, and
• (2) fraction of drug metabolized.
• The latter is usually estimated from 1 – fe;
• alternatively, the fraction of drug metabolized may be estimated from
the ratio of Clh/Cl, where Clh is hepatic clearance and Cl is total body
clearance.

11. PRACTICE PROBLEM
• The hepatic clearance of a drug in a patient is reduced by 50% due to
chronic viral hepatitis.
• How is the total body clearance of the drug affected?
• What should be the new dose of the drug for the patient?
• Assume that renal drug clearance (fe = 0.4) and plasma drug protein
binding are not altered.

12. Active Drug and the Metabolite
• (1) when the drug is more potent than the metabolite, the overall
pharmacologic activity will increase in the hepatic-impaired patient
because the parent drug concentration will be higher;
• (2) when the drug is less potent than the metabolite, the overall
pharmacologic activity in the hepatic patient will decrease because
less of the active metabolite is formed.

13. Hepatic Blood Flow and Intrinsic Clearance
• Blood flow changes can occur in patients with chronic liver disease.
• Hepatic arterial-venous shunts may lead to reduced fraction of drug
extracted and an increase in the bioavailability of drug.
• In other patients, resistance to blood flow may be increased as a
result of tissue damage and fibrosis, causing a reduction in intrinsic
hepatic clearance.

14. • The following equation may be applied to estimate hepatic clearance
of a drug after assessing changes in blood flow and intrinsic clearance
(Clint):

15. Pathophysiologic Assessment
• In practice, patient information about changes in hepatic blood flow
may not be available, because special electromagnetic or ultrasound
techniques are required to measure blood flow and are not routinely
available.
• The clinician/ pharmacist may have to make an empirical estimate of
the blood flow change after examining the patient and reviewing the
available liver function tests.

16. approaches to assess hepatic impairment
• The Child–Pugh (or Child–Turcotte–Pugh) score assesses the overall
hepatic impairment as mild, moderate, or severe (Figg et al, 1995;
Lucey et al, 1997).
• The score employs five clinical measures of liver disease, including
• total bilirubin,
• serum albumin,
• International Normalized Ratio (INR),
• ascites, and
• hepatic encephalopathy

18. • chronic hepatic disease is more likely to change the metabolism of a
drug than acute hepatitis
• Chronic liver disease has been shown to decrease the metabolism of
many drugs as shown in Table 24-13.
• However, the amount of decrease in metabolism is difficult to assess.

20. Hepatic Impairment and Dose Adjustment
• Drugs that have the following properties are less likely to need dosage
adjustment in patients with hepatic impairment (FDA Guidance for
Industry, 2003)
1. The drug is excreted entirely via renal routes of elimination with no
involvement of the liver.
2. The drug is metabolized in the liver to a small extent (<20%), 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.
3. The drug is gaseous or volatile, and the drug and its active metabolites
are primarily eliminated via the lungs.

21. • For each drug case, the physician needs to assess the degree of hepatic
impairment and consider the known pharmacokinetics and
pharmacodynamics of the drug.
• For example, Mallikaarjun et al (2008) studied the effects of hepatic or
renal impairment on the pharmacokinetics of aripiprazole (Abilify), an
atypical antipsychotic used to treat schizophrenia. These investigators
concluded that there were no meaningful differences in aripiprazole
pharmacokinetics between groups of subjects with normal hepatic or renal
function and those with either hepatic or renal impairment. Thus, the
adjustment of the aripiprazole does not appear to be required in
populations with hepatic or renal impairment.

22. • In contrast, Muirhead et al (2002) studied the effects of age and renal and
hepatic impairments on the pharmacokinetics, tolerability, and safety of
sildenafil (Viagra), a drug used to treat erectile dysfunction. Muirhead et al
(2002) observed significant differences in Cmax and AUC between the
young and the elderly subjects for both the parent drug and the
metabolite. In addition, the hepatic impairment study demonstrated that
pharmacokinetics of sildenafil was altered in subjects with chronic stable
cirrhosis, as shown by a 46% reduction in CL/F and a 47% increase in Cmax
compared with subjects with normal hepatic function. Sildenafil
pharmacokinetics was affected by age and by renal and hepatic
impairments, suggesting that a lower starting dose of 25 mg should be
considered for patients with severely compromised renal or hepatic
function.

23. Adjustment based on Child-Pugh score
• The Child-Pugh score for a patient with normal liver function is 5
• while the score for a patient with grossly abnormal serum albumin,
total bilirubin, and prothrombin time values in addition to severe
ascites and hepatic encephalopathy is 15.

24. • A Child-Pugh score equal to 8-9 is grounds for a moderate decrease (∼
25%) in initial daily drug dose for agents that are primarily (≥60%)
hepatically metabolized,
• and a score of 10 or greater indicates that a significant decrease in initial
daily dose (∼ 50%) is required for drugs that are mostly liver metabolized.
• As in any patient with or without liver dysfunction, initial doses are meant
as starting points for dosage titration based on patient response and
avoidance of adverse effects.

25. • For example, the usual dose of a medication that is 95% liver
metabolized is 500 mg every 6 hours, and the total daily dose is 2000
mg/d.
• For a hepatic cirrhosis patient with a Child-Pugh score of 12, an
appropriate initial dose would be 50% of the usual dose or 1000
mg/d. The drug could be prescribed to the patient as 250 mg every 6
hours or 500 mg every 12 hours. The patient would be closely
monitored for pharmacologic and toxic effects due to the medication,
and the dose would be modified as needed.