Mini-Review

Drug Dosing in Renal Disease

*Matthew P Doogue,1,2 Thomas M Polasek1
1
Department of Clinical Pharmacology, Flinders University, 2Flinders Medical Centre, Bedford Park, SA 5042, Australia.
For correspondence: Dr Matt Doogue, matt.doogue@health.sa.gov.au

Abstract
Renal disease alters the effects of many drugs, particularly when active drug moieties are renally cleared. Drug doses should
usually be reduced in renal disease in proportion to the predicted reduction in clearance of the active drug moiety. Patient factors
to consider in adjusting drug doses include the degree of renal impairment and patient size. Drug factors to consider in adjusting
doses include the fraction of the drug excreted unchanged in urine and the drug’s therapeutic index. Estimates of renal function
are useful to guide dosing of renally cleared drugs with medium therapeutic indices, but are not precise enough to guide dosing
of drugs with narrow therapeutic indices. This article discusses principles of drug dose adjustment in renal disease.

Introduction estimate renal function, in diagnosing renal disease and

Renal disease alters the effects of many drugs, sometimes
decreasing their effects but more often increasing their
effects and thus potential toxicity. Many of these changes are
predictable and can be mitigated by changing drug doses.
Renal disease interacts with drugs in three main ways.
Firstly, patients with renal disease may be more vulnerable
to a given drug effect (patient susceptibility). Secondly, a
drug effect may be exaggerated or attenuated in patients
with renal disease (pharmacodynamic change). Thirdly,
and most importantly, some drugs have higher steady-state
concentrations when given at usual doses to patients with renal
disease (pharmacokinetic changes). This article describes
how to adjust drug dose to account for the pharmacokinetic
changes that occur in renal disease.
This can be summarised in one sentence: The drug dose
should be reduced proportionally to the predicted reduction
in drug clearance.
Increased drug clearance results in lower drug concentrations,
while decreased drug clearance results in higher drug
concentrations and hence greater drug effects. To avoid harm
when drug clearance is significantly decreased, the dose of
renally cleared drugs should usually be reduced in patients
with renal disease.
Estimates of GFR Based on Creatinine
Estimates of glomerular filtration rate (GFR) are used to
are also used to estimate renal drug clearance. Some active
drug moieties are wholly or partly cleared from the body
by the kidneys and this is the physiological rationale for
using eGFR to estimate drug clearance. Similar to serum
drug concentration, serum creatinine is dependent on both
creatinine production (equivalent to drug dose) and creatinine
clearance (equivalent to renal drug clearance).
Serum creatinine is the most commonly used analyte in the
evaluation of renal function, and equations using serum
creatinine concentration are the basis of most estimates of
GFR (as discussed in detail elsewhere in this issue).1 Estimated
GFR (eGFR) has the units mL/min/1.73m2,2 whereas
creatinine clearance and drug clearance are both measured in
mL/min. To avoid confusion, units should be carefully noted
and their implications considered. This is discussed in more
detail below.
Drug Dosing
The units of drug dose are amount per unit time e.g. 500
mg twice daily. For most drugs, prescribing information
recommends a standard dose and provides some guidance
on when this should be changed.3 The advice is necessarily
imprecise as most drugs have large inter-individual variability
in clearance and response. Consequently, dose adjustment is
crude for most drugs in most circumstances, for example by
doubling or halving doses. This is reflected in the available
drug preparations, with most provided in a limited number of
strengths which limits dose adjustment options. In most cases

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Doogue MP & Polasek TM

having a means to identify when drug dose should be halved
or doubled is important, whereas a 20% change in dose is
usually impractical or unnecessary. However there are several
drugs for which small changes in dose or concentration may
have an important effect, commonly known as a narrow
therapeutic index.
Therapeutic Index
minimum toxic dose
The therapeutic index =
minimum effective dose
For drugs with narrow therapeutic indices (Table 1), a small
change in drug concentration can cause toxicity or loss of
efficacy. Narrow therapeutic index drugs should be dosed using
robust biomarkers, as estimates or empirical calculations of
dose are not reliable enough to be safe. For example, lithium
is a renally cleared drug with a narrow therapeutic index;
therapeutic drug monitoring is used together with clinical
response to guide dosing. Warfarin is a narrow therapeutic
index drug that is metabolised rather than renally cleared;
international normalised ratio (INR) is used as a biomarker
to guide dosing.
the steady state plasma concentration (Cp) at a given dose
(Equation 1 and Figure). CL has the units of volume/time and
F is dimensionless (%). Note that CL is not the same as drug
elimination (which, like dose, has units of amount/time and
becomes equal to dose at steady state).
Equation 1:
units of equation 1:
From Equation 1 it can be seen that if CL is halved, drug dose
should be halved to keep the drug concentration the same.
Thus, if a drug is 100% renally cleared and renal function
is half-normal, the drug dose should be halved, all other
things being equal. However, many drugs are inactivated by
metabolism (in the liver predominantly), and hence doses of
metabolised drugs do not usually require changing in renal
disease.

Conversely, for drugs with a wide therapeutic index, even

large changes in drug clearance may have only a modest
impact on response, and therefore dose adjustments are less
important. Beta-lactam antibiotics constitute a class of renally
cleared drugs with wide therapeutic indices.

Drugs with narrow therapeutic indices should be dosed using
biomarkers of effect and/or therapeutic drug monitoring.
Drug Clearance
Drug clearance (CL) and bioavailability (F) (the fraction of
the drug dose that reaches the systemic circulation) determine
Figure. Pharmacokinetics: the relationship between drug dose,
drug concentration and pharmacokinetic variables. Adapted
from Begg.4 CL = (apparent) clearance; F = bioavailability;
Cp = steady state plasma concentration; Vd = (apparent)
volume of distribution; k = elimination rate constant; t½ =
elimination half-life.

Table 1. Examples of drugs with narrow therapeutic indices.

Renally Cleared Metabolised

Aminoglycosides amikacin Anticoagulants warfarin (INR)*

gentamicin Anticonvulsants lamotrigine
Glycopeptides vancomycin phenytoin
Other digoxin Cardiac drugs amiodarone
lithium perhexiline
morphine 6-glucuronide Hormones insulin (glucose)*
thyroxine (TSH)*
Immunosuppressants mycophenolate
tacrolimus

*items in brackets represent recommended biomarker for dose titration.

Doses of these and other narrow therapeutic index drugs should be based on clinical response, biomarkers of effect and/or drug
concentrations; empirical dose estimates are not sufficiently robust. Note that these are examples only and that this is not a
comprehensive list.

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Drug Dosing in Renal Disease

There are some drugs that are partially cleared by the
kidneys and partially metabolised (e.g. low molecular weight
heparins). For these drugs the dose reduction needed in renal
disease is less than that for drugs that are 100% renally cleared.
For example, in a patient with half-normal renal function, the
dose of a drug that is half renally cleared and half metabolised
would typically need to be reduced by a quarter.
Fraction Excreted Unchanged
The fraction excreted unchanged (fe) is the proportion of the
active drug cleared renally in an average healthy person. The
doses of drugs with fe ≥0.5 (50% or more renally cleared)
should usually be reduced in patients with renal disease.
This is particularly important for drugs with an intermediate
therapeutic index (Table 2).
Equation 2:
patient dose =
usual dose x ((1 – fe) + fe x
From Equation 2 it follows that dose should be reduced in
proportion to a patient’s relative renal function for drugs that
are 100% renally cleared, all other things being equal. The
calculated dose can usually be rounded to the nearest whole
or half tablet or the dose interval can be changed.
Estimates of Renal Function
For chronic kidney disease, estimates of renal function are
used to predict disease outcome. However for drug dosing,
estimates of renal function are used to estimate the renal
clearance of the drug in question. When evaluating estimates
of renal function for prescribing guidelines it is important
to consider the gold standard of drug effect or, alternatively,
drug concentration. Pharmacokinetic studies in patients with
renal disease are usually conducted as part of preregistration
evaluation. While not all these studies are published in peer-
reviewed journals, the results can usually be obtained from
the US Food and Drug Administration (FDA) databases.5
Patient size is a particularly important factor to consider
when using creatinine-based estimates of renal function. The
units of drug clearance are volume/time (mL/min), whereas
the units of eGFR for chronic renal disease are volume/time/
standard size (mL/min/1.73m2). How to consider the effect of
size in drug dosing is discussed in detail elsewhere and has
been the subject of interventional studies.6-8 This aspect is a
major limitation in using eGFR for drug dosing.
In many other respects the limitations of using creatinine-
based measures both for drug dosing and for monitoring renal
disease are similar. For example, creatinine-based estimates
of renal function are not reliable in pregnancy. Methods of
estimating renal function are discussed elsewhere in this
journal.1,9
Drug Product Information
Each drug is registered with product information for
prescribers which encapsulates large amounts of research
specific to that drug. When dosing advice for renal impairment

Table 2. Examples of drugs with fraction excreted unchanged (fe) ≥0.5.

Intermediate therapeutic index drugs fe

acyclovir and related antivirals 0.6–1

allopurinol 1 (oxypurinol)
atenolol 1
dabigatran 0.9
DPP-IV inhibitors* (e.g. sitigliptin) 0.8–1
gabapentin and pregabalin 1
low molecular weight heparins 0.7
metformin 1
morphine-6-glucuronide** 1

Wide therapeutic index drugs

ACE inhibitors† 1
beta-lactam antibiotics†† 0.7–1
carbapenems 0.6–1

* Dipeptidyl peptidase-IV inhibitors, used in treating type 2 diabetes.

** The major active metabolite of morphine.
†
Most angiotensin-converting enzyme (ACE) inhibitors are prodrugs (suffix -pril, e.g. enalapril) of a renally cleared active
moiety (suffix -prilat, e.g. enalaprilat).
††
With some exceptions e.g. ceftriaxine with fe ~ 0.5.

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Doogue MP & Polasek TM
is provided in the product information, it is important to
know what method of defining renal impairment is used in
that particular product information if a patient’s dose is to be
reviewed. In most cases it is calculated creatinine clearance
using the Cockcroft and Gault equation,10 as for many years
this has been recommended by the FDA for pharmacokinetic
calculations.11 Although this situation may change, at the time
of writing the Cockcroft and Gault equation underpins the
majority of drug product information.
It should also be noted that product information sheets often
have only crude dosing guidelines for renal impairment
and sometimes specifically exclude patients with renal
impairment (usually because these patients were excluded
from the primary studies). In these situations, applying first
principles is the only option if the drug is to be used, and
such considerations allow for more appropriate prescribing in
many situations. For example, a small change in creatinine
clearance (or eGFR) from 31 mL/min to 29 mL/min may
appear to cross a treatment threshold (of 30 mL/min) but be
due solely to imprecision of measurement. Applying the letter
of the product information may result in a large change in
dose or stopping the drug altogether, whereas in reality the
dose may not need changing.
Examples
Lithium is used primarily in the treatment of bipolar disorder
and is 100% renally cleared. It has a narrow therapeutic index.
An estimate of renal function helps select a starting dose for
treatment. Subsequent dosing should be guided by measured
drug concentrations and clinical response. Estimates of renal
function can also be helpful in interpreting drug concentrations
(e.g. assessing whether a low concentration is due to under-
dosing or poor compliance).
The anti-gout drug allopurinol is the prodrug of oxypurinol
which is 100% renally cleared. It has an intermediate
therapeutic index. An estimate of renal function as an estimate
of drug clearance provides useful guidance to dosing and can
be used together with clinical and biochemical measures of
effect (e.g. serum urate concentration).
Amoxicillin is a beta-lactam antibacterial drug that is 100%
renally cleared. It has a wide therapeutic index. It is usually
used acutely i.e. short-term. Most dosing guidelines do
not discriminate on the basis of renal clearance except for
patients with end-stage renal disease. Estimates of renal
function are helpful in identifying patients who may need
shorter dose intervals (high clearance) or may be adequately
treated with smaller dose amounts or longer dose intervals
(low clearance).
72 I Clin Biochem Rev Vol 32 May 2011
Compliance
No discussion on drug dosing is complete without a mention
of compliance. Compliance is the greatest cause of therapeutic
failure in the treatment of chronic diseases.12 In prescribing
any drug, the possibility of current or future non-compliance
with the prescribed regimen should be considered. For
example, a low digoxin concentration may be due to either
underdosing or appropriate dosing with poor compliance.
An estimate of GFR together with the digoxin concentration
helps to discriminate between these two possible causes of
treatment failure.
Other Information
The effects of other variables that may influence drug dosing
in renal disease, such as changes in urine pH and the role
of drug transporters for secretion, are beyond the scope
of this article. Further information can be found in clinical
pharmacology textbooks (such as Begg,4 Goodman and
Gilman,13 and Cervelli14) or the primary literature. Online
resources are increasingly available for further learning.15-17
Conclusion
Important variables relevant to prescribing decisions are often
not recognised in clinical care. The primary message of this
article is that renal function is an important physiological
variable that predictably affects the pharmacokinetics and
thus clinical effectiveness of some drugs. Recognition of
renal function as a prescribing issue is more important than
the precision of different estimates of renal function. When
prescribing for a patient with decreased renal function the
characteristics of both the patient and the drug should be
considered.
Principles that can be applied to any drug dosing situation
have been described in this article. These are predicated on
pharmacokinetic principles, patient physiology and skill in
utilising drug information. Drug prescribing protocols do not
cover all scenarios. Understanding and applying principles
of good prescribing, such as those outlined above, allow
recognition of potential problems, avoidance of drug toxicities
and improvements in treatment efficacy.
Competing Interests: None declared.
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