19 Hepatic and Renal Failure

Anthony W. Fox

Drug development programs are obligated to
consider whether specific dose adjustments,
warnings or contraindications should be recom-
mended in patients with varying degrees of hepa-
tic or renal failure. In some regards the issues are
analogous for patients with disease in one or
other of these organs, and, indeed, renal failure
can be secondary to hepatic disease (the reverse
is more controversial). The objective here is to
review the issues surrounding these special popu-
lations. In doing so, readers should also review
the two excellent US Food and Drug Adminis-
tration (US FDA) Guidances on these subjects
(see Further reading list at the end of this
chapter).

19.1 General principles

(a) The issues surrounding hepatic or renal insuf-
ficiency are obviously greater for drugs (or
their active or toxic) metabolites that are elimi-
nated by the liver, kidney or both.

(b) From a safety perspective, drugs whose effec-
tive doses are close to the harmful dose

(a narrow ‘therapeutic ratio’) are more likely

to have critical limits on exposure, and thus,

in general, more likely to need careful study in

patients with disease in these organs. A useful

rule of thumb is: ‘If there is going to be a clini-

cal assay for the drug, then watch out for renal

and hepatic disease associated adverse effects’.

(c) Both renal and hepatic function can decline

with age and differ with gender, pregnancy

and so on. When studies are needed (see

below), the appropriate controls are not the

typical young, fit normal volunteers in phase

I studies, but rather people who are age- and

sex-matched as closely as possible to the

patients with the disease state that will form

the indication for the drug.

(d) Population kinetics can often provide much

useful information, especially when the

intended patient population is elderly and

may well have varying degrees of hepatic or

renal reserve within the ordinary phase III

database. This requires documentation of

each patient’s hepatic and renal status in ordin-

ary clinical trials of unrelated diseases,

Principles and Practice of Pharmaceutical Medicine, 2nd Edition Edited by L. D. Edwards, A. J. Fletcher, A. W. Fox and P. D. Stonier
#2007 John Wiley & Sons, Ltd ISBN: 978-0-470-09313-9