Principles and Practice of Pharmaceutical Medicine

children is:

Under 1 year : CrCLðml min
^1 Þ¼

½ 0 : 45 lengthðcmފ=serum creatinineðmg dl
^1 Þ

1 
12 years : CrCLðml min
^1 Þ¼

½ 0 : 55 lengthðcmފ=serum creatinineðmg dl
^1 Þ

Dialysis

Lastly, end-stage renal disease is characterized by
the need for routine dialysis. These are the patients
with renal failurefor whom an increase in dosing
may be necessary to compensate for drug/active
metabolites being lost into the dialysate. Under-
standing the pharmacokinetics of the drug during
dialysis is essential unless it is not anticipated that
such patients will be treated with it. Even then,
knowing whether a drug can or cannot be dialyzed
is helpful in providing advice to clinicians dealing
with overdoses or poisonings after the drug has
been marketed.

Labeling

The US FDA Guidance provides several specimen
pieces of wording for use by those drafting product
labeling. They are highly recommended. Generally
speaking, if renal insufficiency causes a change in
pharmacokinetics that exceeds the latitude granted
to generic copies of previously approved drugs,
then careful consideration to adding specific dos-
ing recommendations for patients with renal insuf-
ficiency to the product labeling. Currently, this
latitude is for the meanCmaxto lie outside a
range of 70–143% of the control mean, with the
simultaneousmean AUC to lie outside 80–125%of
the control mean.

19.3 Hepatic insufficiency

Many of the guiding principles offered above for
renal insufficiency find their corollaries in hepatic
insufficiency. However, there are two fundamental

differences. Firstly, hepatic disease causes second-

ary renal failure more often than the other way

round. Secondly, it is more difficult to quantify

severity of insufficiency of the liver than for the

kidney. This section of the chapter is again based

upon the excellent US FDA Guidance (see Further

reading below).

The literature contains literally hundreds of

reports on the influence of liver disease on drug

elimination. Most commonly the patients in these

studies have various degrees of fatty degeneration

or cirrhosis (the former often associated with

alcohol or diabetes, and the latter most commonly

due to hepatitis viruses, alcohol, but sometimes

obliterative biliary disease or autoimmune dis-

ease). These diseases are more often associated

with intrinsic alterations in pharmacodynamic

responses, for example liability to seizure is com-

mon in patients suddenly withdrawn from chronic

alcohol abuse, and the encephalopathy associated

with elevated circulating concentrations of ammo-

nia or superimposed acute hepatic disease or gas-

trointestinal bleeding.

Assessing severity of hepatic

dysfunction

Mostwidelyacceptedbyregulatoryauthorities(i.e.

you have to have a good reason not to use it) is the

Child-Pugh scoring system. This was originally

developed as a method for assessing anesthesia/

surgical hazard in patients with varying degrees

of hepatic disease. It is a point-scoring system,

according to Table 19.1.

The only other commonly used alternative is

the Maddrey Discriminant Function (MDF)

which was developed to assess acute alcoholic

hepatitis. This is more easily calculated than the

Child-Pugh score as:

MDF¼½ 4 : 6 prothrombin timeðsފ

þserum total bilirubinðmg dl
^1 Þ

Disease was labeled not severe when MDF<54,

severe at 55–92 and probably lethal at93. In

practice, most modern clinical trials will document

252 CH19 HEPATIC AND RENAL FAILURE