Principles and Practice of Pharmaceutical Medicine

although each patient may provide only a

sparse set of pharmacokinetic samples.

(e) For drugs administered chronically, consider
carefully whether single-dose pharmacoki-
netics are truly predictive of the multiple-
dose situation, not only in normal volunteers
but also in patients with hepatic or renal dis-
ease. In case of any doubt, conduct the studies
described below in patients with liver or kidney
disease at steady state, or at least under condi-
tions where the effects of the organ insuffi-
ciency can be assessed at both peak and
trough drug concentrations.

(f) Be aware thatpharmacokinetics andpatterns of
metabolism can change in patients with hepatic
and renal insufficiency. With serious liver dis-
ease, many drugs’ eliminations convert from
first-order to zero-order. With serious renal
disease, new metabolites may appear in the
circulation because the urinary excretion of
unchanged drug or the fastest generated meta-
bolites is reduced. Dialysis often causes the
opposite phenomenon.

(g) There is a need to study the effect ofvarying
degreesof hepatic or renal sufficiency on new
drugs, according to the relevance of every
degree to the promulgated indications. Almost
all new drugs that will be administered to per-
sons over 65 years of age will therefore need
information about the effects ofmildrenal or
hepatic insufficiency. Additionally, some drugs
may need to be studied in patients withmod-
erate or severeinsufficiency(ies). In general, it
is easier to quantify degree or severity of renal
failure than hepatic failure.

(h) For drugs that are excreted entirely and
unchanged by the lung (e.g. inhaled anesthetic
gases), it is almost always possible to provide a
rationale that hepatic and renal insufficiency
studies are unnecessary. Similar arguments can
often be made for single-dose drugs with wide
margins between dose–response curves for
wanted and unwanted effects, even if elimi-
nated by either the kidney or the liver.

19.2 Renal insufficiency

The central question is whether the degree of renal

insufficiency that exists in patients who are likely

to be exposed to the drug of interest could have a

sufficient effect as to warrant an alteration in dos-

ing. Note that the kidney is also an organ of meta-

bolism, and, therefore, renal disease (especially

when severe) can affect clearance in multiple

ways, not just in urinary excretion.

Are studies needed?

The resolution of this central question, and thus the

perceived need for special studies, hinges on multi-

ple factors:

(a) Is the reduced excretion likely to cause a phar-

macokinetic effect that is likely to be asso-

ciated with a deleterious pharmacodynamic

effect (reductionin efficacyor increasein intol-

erability)?

(b) Is the drug and its indication likely ever to be

administered to people with renal insuffi-

ciency, and, if so, then to what degree of the

latter?

(c) Is there an active metabolite for which these

considerations are more important than the

parent drug?

(d) Can fluid overload or other factors that change

plasma protein concentration, and hence bind-

ing, interact with the anticipated effects on

renal excretion?

(e) Are there some rare, special factors that can

even theoretically be imagined (e.g. drug-

induced diabetes insipidus and lithium)?

Excluding an effect of renal failure

It is usually straightforward to conduct brief stu-

dies confirming the absence of any effect of renal

failure that would impact pharmacodynamics. This

250 CH19 HEPATIC AND RENAL FAILURE