Dosing of Gentamicin in Patients With
End-Stage Renal Disease Receiving
Hemodialysis
Mette Maja B. Teigen, BPharm, MClinPharm, Stephen Duffull, MPharm, PhD,
Lily Dang, BPharm(Hons), and David W. Johnson, MBBS, FRACP, PhD
The aim of this study was to evaluate dosing schedules of
gentamicin in patients with end-stage renal disease and
receiving hemodialysis. Forty-six patients were recruited
who received gentamicin while on hemodialysis. Each
patient provided approximately 4 blood samples at vari-
ous times before and after dialysis for analysis of plasma
gentamicin concentrations. A population pharmacokinetic
model was constructed using NONMEM (version 5). The
clearance of gentamicin during dialysis was 4.69 L/h and
between dialysis was 0.453L/h. The clearance between
dialysis was best described by residual creatinine clearance
(as calculated using the Cockcroft and Gault equation),
T he mortality rate among patients with end-stage
renal disease (ESRD) in the Western world is high
(16%-22%),1,2 with infection being the second most
common cause of death in this patient group. Sep-
ticemia accounts for approximately 75% of this infec-
tion rate in the United States, and mortality from
sepsis is higher when compared to the general popu-
lation, even when stratifying for other risk factors.3
Surprisingly, after more than 50 years of clinical
experience with aminoglycosides, many aspects with
regard to their use remain unresolved. When pre-
scribing aminoglycoside antibiotics to patients with
ESRD, it appears to be common practice to administer
the drug after the patient has received hemodialysis.
From the School of Pharmacy, University of Queensland, Brisbane, Australia
(Ms Teigen, Dr Duffull, Ms Dang); Diakonhjemmet Hospital Pharmacy,
Oslo, Norway (Ms Teigen); the Department of Renal Medicine, University
of Queensland at Princess Alexandra Hospital, Brisbane, Australia
(Dr Johnson); and the School of Pharmacy, University of Otago, Dunedin,
New Zealand (Dr Duffull). Submitted for publication February 19, 2006;
revised version accepted July 13, 2006. Address for correspondence:
Stephen Duffull, MPharm, PhD, School of Pharmacy, University of Otago,
Dunedin, New Zealand; e-mail: stephen.duffull@stonebow.otago.ac.nz.
DOI: 10.1177/0091270006292987
J Clin Pharmacol 2006;46:1259-1267
which probably reflects both lean mass and residual clear-
ance mechanisms. Simulation from the final population
model showed that predialysis dosing has a higher proba-
bility of achieving target maximum concentration (Cmax)
concentrations (>8 mg/L) within acceptable exposure limits
(area under the concentration-time curve [AUC] values >70
and <120 mg·h/L per 24 hours) than postdialysis dosing.
Keywords: Aminoglycosides; hemodialysis; end-stage
renal disease; pharmacokinetics
Journal of Clinical Pharmacology, 2006;46:1259-1267
©2006 the American College of Clinical Pharmacology
Emerging data and theoretical considerations suggest
this may not be the most beneficial manner of admin-
istration.4 Over recent years, a more complete under-
standing of the pharmacokinetic-pharmacodynamic
relationships of aminoglycosides has led to a global
change in clinical practice from multiple to once-daily
dosing. Relevant pharmacokinetic-pharmacodynamic
aspects of aminoglycosides include bactericidal activ-
ity that is linked to Cmax (efficacy improves with
higher peak concentrations),5-8 adaptive resistance that
is reversed by an adequate interval of low drug con-
centration between doses,9-12 and exposure-dependent
toxicity.13-16
Most once-daily dosing regimens are based on
achieving an equivalent exposure (area under the
concentration-time curve [AUC]) to that which would
have been achieved with divided doses; thus, it is
suggested that the risk of toxicity should be no higher
when the dose is administered once daily.17,18 The
pharmacokinetic-pharmacodynamic behavior of
aminoglycosides that led to longer dose intervals with
higher Cmax values also strongly supports adminis-
tration of these agents before hemodialysis. The
overall pharmacokinetic-pharmacodynamic goal
1259
 TEIGEN ET AL
when prescribing aminoglycosides in hemodialysis
patients is to achieve a concentration-time profile
that approaches the profile seen after once-daily dos-
ing in patients with normal renal function. In doing
this, it is believed that the benefits of aminoglyco-
sides when used in patients with normal renal func-
tion can be conferred to those receiving hemodialysis.
It is hypothesized that dosing of aminoglycosides
prior to, rather than after, hemodialysis will allow for
a higher dose to be administered for any given level
of exposure and hence provide higher peak concen-
trations.4 Predialysis dosing has been supported based
on simulations from a semimechanistic model describ-
ing the influence of ESRD and hemodialysis on the
pharmacokinetics of aminoglycosides.19 The subse-
quent dialysis session provides clearance of the drug
that approaches that of patients with normal renal
function and leads to lower concentrations prior to
administering the next dose so that exposure (AUC)
is reduced. It also remains possible that the amino-
glycoside could be administered during the initial
stage of dialysis to decrease waiting time. This con-
cept has been tried previously with vancomycin.20
Only one published article that described the pro-
file of aminoglycosides when administered predialysis
was found. In this study of arbekacin in 10 patients,4
dosing prior to dialysis appeared to produce an AUC
of approximately 40% that of the AUC when the same
dose was given postdialysis. The aim of the current
study was to evaluate dosing schedules of gentamicin
in patients with ESRD and receiving hemodialysis.
METHODS
The study consisted of three phases: (1) data col-
lection (prospective and retrospective), (2) model
development and evaluation using the collected
pharmacokinetic data, and (3) investigation of dos-
ing schedules.
Study Population
The study patients were enrolled prospectively from
the Princess Alexandra Hospital, a tertiary referral
hospital in Brisbane, Australia. Patients were eligi-
ble if they were enrolled in the hemodialysis program
and were receiving gentamicin to treat a suspected
or proven infection. Because of recruitment difficul-
ties, some patients were also enrolled retrospectively.
Patients were studied on the dosing they happened
to be receiving at the time they presented (regardless
of time of dosing in relation to dialysis), and they were
eligible for inclusion both on first and subsequent
doses of gentamicin. Patients were excluded if they
1260 • J Clin Pharmacol 2006;46:1259-1267
had been on the dialysis care program for less than 1
month.
Data Collection
Collected data included dose, dose interval, the tim-
ing of all doses, the infusion time, the time of blood
samples, and the subsequent concentrations of gen-
tamicin, start and stop times for hemodialysis ses-
sions, blood flow to the dialyzer, dialyzer filter
thickness, surface area, dialysate rate, and amount of
fluid to be removed. Demographic data collected
included age, sex, weight (immediately after dialysis
when possible), height, and a predialysis creatinine
concentration. Creatinine clearance (CLCR) was approx-
imated with the Cockcroft and Gault formula21 using
a predialysis plasma concentration of creatinine and
ideal body weight,22 as determined by height.23 This
is an easily available approximation, which has
numerous limitations that are especially relevant in
this patient group.24-27 Thus, the CLCR descriptor is
not intended to reflect true residual renal function
but rather to provide an overall descriptor of the
patients’ functional status. It is likely that CLCR is a
marker of lean mass and nonrenal mechanisms for
clearance of creatinine in this setting.
Ethics
The study was reviewed and approved by the Princess
Alexandra Hospital Research Ethics Committee before
patient involvement commenced. Prospective patients
provided written informed consent before joining the
study.
Pharmacokinetic Sampling
Four blood samples were taken from most prospec-
tively enrolled patients. The first blood sample for the
study was taken by venipuncture at approximately 30
minutes after the end of the infusion of the study
dose of gentamicin. This blood sample represents an
approximation to Cmax. Three further blood samples
were collected from each patient to establish plasma
concentrations of the aminoglycoside antibiotic and
clearance within and between dialysis sessions. Typ-
ically, this involved a blood sample at the beginning
of dialysis, a blood sample at the end of dialysis
(both taken from the dialysis machine), and an inter-
dialytic blood sample taken prior to the next dialysis
session. Any additional blood samples that were taken
as a part of routine clinical care were also used for
data analysis. For the retrospective component of the
 GENTAMICIN IN PATIENTS WITH ESRD RECEIVING HEMODIALYSIS
study, blood samples were available from the comput-
erized patient records as a part of usual clinical care.
Gentamicin plasma concentrations were determined
using the Bayer Advia Centaur assays. The between-
run coefficient of variation has been estimated as
7.4% at 2.2 mg/L and 5.9% at 6.5 mg/L. The lowest
level of detection was 0.3 mg/L.
Population Analysis
A model was developed using the first-order condi-
tional estimation method (FOCE) with the interaction
option in NONMEM (version 5). The model fit was
evaluated by considering the value of the objective
function, parameter estimates, their between-subject
variability (BSV), and visual inspection of diagnostic
plots. Pharmacokinetic parameters for the patient
population were estimated, such as interdialytic clear-
ance (termed nonhemodialysis CL [CLNHD]), clearance
during hemodialysis (CLHD), apparent volume of dis-
tribution (Vd), BSV of the estimates, and variance of
the residual uncertainty. It was assumed that the elim-
ination of gentamicin during dialysis was mediated by
a first-order process. The NONMEM covariance com-
mand was used to obtain standard errors of the
estimates. Model fit was assessed by the likelihood
ratio test, where it is assumed that the difference of
2 NONMEM objective function values for nested
models is asymptotically and approximately χ2 dis-
tributed. Under this assumption, the likelihood ratio
test at α = .05 significance level was used as a guide
to statistical significance for model discrimination
and a reduction of more than 3.84 units in the objec-
tive function is considered significant for models with
1-parameter difference (χ2, P < .05). Hemodialysis
was considered an essential covariate, and therefore
a base hemodialysis model was established before
other covariates were considered.
Inclusion of covariates into the model was based
on 4 criteria: (1) the parameter values produced by
the covariate model had to be biologically plausible;
(2) inclusion of the covariate into the model led to a
significant drop in the objective function of 3.84
points or more; (3) the inclusion of the covariate pro-
duced a drop in the unexplained between-subject vari-
ance; and (4) the observed change in the parameter
values as a result of the covariate inclusion were
clinically significant (eg, >20% change in the para-
meter value given the range of covariate values). The
model was specified as an ordinary differential
equation, with a time-related switch that adjusted
clearance due to start and stop times for hemodialy-
sis. Volume of distribution was also allowed to incre-
ment during the interdialytic interval associated with
PHARMACOKINETICS
an accumulation in extracellular fluid. The statistical
model for the data was given by additive, propor-
tional, or combined errors (combined error shown):
yij = f(θi, xij)e ε1ij + ε2ij
where yij is the jth observed concentration for the ith
individual and f(θi, xij) is the model-predicted concen-
tration, ε1ij is the proportional residual error, and ε2ij is
the additive residual error. It is assumed that ε1ij and ε2ij
are independent and identically distributed of the
form ε ~ N(0, σ 2). The statistical model for BSV was
θi = θe ηi
where ηi represents a vector of differences between
the ith individual parameter estimates from the pop-
ulation parameter values. It is assumed that η are
independent and identically distributed with mean
zero and variance-covariance (Ω).
Evaluation of Dosing Schedules
The desirable targets when administering gentam-
icin to adult patients with normal renal function are
Cmax greater than 10 mg/L and a 24-hour AUC between
70 and 120 mg·h/L.17 For the purpose of this patient
population, a lower Cmax target of 8 mg/L was con-
sidered a success, thus accounting for a necessary
dose reduction in patients with ESRD when admin-
istering aminoglycoside antibiotics. The value of
8 mg/L is also the concentration target for conven-
tional multiple daily dosing.17 A maximum 24-hour
AUC value of 120 mg·h/L was chosen, as this repre-
sents the upper limit proposed by Begg et al,17 rather
than the more usual 100 mg·h/L for patients who
have normal to moderately impaired renal function.
Therefore, treatment success was based on achiev-
ing a success in each of the following 3 criteria,
assuming a 48-hour dialysis schedule:
1. Cmax ≥8 mg/L
2. AUC ≥140 mg·h/L/48 h
3. AUC ≤240 mg·h/L/48 h
The final covariate model was used to simulate
various dosing schedules. MATLAB (version 6.0.0.88,
release 12) was used to perform simulations for 1000
virtual patients for each proposed dosing schedule.
Three doses administered over a treatment period of
6 days were simulated for each virtual patient, where
hemodialysis was administered every 48 hours. We
did not include a 72-hour interdialytic period once per
week, as would commonly be the case in clinical
1261
 TEIGEN ET AL

Table I Patient Characteristics years; there were 23 women and 23 men. Character-
istics of the study subjects are shown in Table I.
Patient Characteristic Mean ± SD
High-flux polysulfone membranes were the most com-
(n = 46) (range) or %
monly used dialyzer (used in approximately 59% of
Male 50 patients), followed by low-flux polysulfone mem-
Age, y 57.3 ± 17.3 (18-83) branes (used in 41% of patients). Filter types are
Height, cm 164.7 ± 11.6 (135-195) provided in the appendix. The mean blood flow rate
Weight, kga 72.4 ± 17.2 (42.1-100.5) was 14.6 L/h and dialysate flow rate was similar for
CLCR, L/hb 0.53 ± 0.2 (0.26-1.24) all patients in the study (≈30 L/h).
No. of blood samples 4.6 ± 2.2 (1-10)
Dialysis details Population Analysis
Blood flow rate, L/h 14.6 ± 2.2 (10.8-15.3)
Duration of dialysis, h 4.1 ± 0.5 (2-5) A zero-order input 1-compartment model with log nor-
Interdialytic period, h 47 ± 19.9 (20-102) mal BSV of CL and Vd and a combined proportional
Time since starting 22.4 ± 29.5 (1-144) and additive error provided the best fit to the data and
dialysis, mo
was chosen as the best base model. Hemodialysis was
a. Dry weight. the most appropriate first step to improve model fit,
b. Calculated using the Cockcroft and Gault formula using ideal body and the incorporation of hemodialysis resulted in a
weight.
drop in the objective function value of 69 points (see
Table II for parameter values). Between-subject vari-
practice. An extended break would not affect the inter- ability was only included for CLNHD and Vd, because
pretation of the simulations because it would serve the data set did not support its inclusion for CLHD. A
only to increase the success rate across all dosing reg- more mechanistic model, which included a factor for
imens for 1 dose interval. The primary outcome mea- dialysis clearance taking into account differences in
sures were peak concentration of aminoglycoside dialyzer filter thickness, surface area of the mem-
(Cmax) and AUC. Treatment success in 1 of the crite- brane, intrinsic clearance, and blood flow was not
ria was denoted by an indicator variable set to 1, and explored, because no random effect could be esti-
treatment failure was set to 0. With 3 administered mated for CLHD and hence no improvement in model
doses and 3 indicator variables, an overall success fit could occur. We did however assess the influence
for a virtual patient was provided by the product of of adding the filter type (high- or low-flux) into the
the 9 indicator variables. Success rates for the sepa- model that had a BSV term for CLHD. This resulted in
rate criteria for individual doses were also consid- a 9% increase in CLHD for the high-flux filters com-
ered. The best dosing schedule was one that provided pared to low-flux. However, this was not statistically
the highest likelihood of overall success (in all cate- significant, and filter type was not retained in the
gories on all doses). Execution variability was incorpo- model. The indicator covariate CLCR was the only
rated into the simulation model to account for variable influential covariate (for CLNHD) and resulted in a drop
times of starting hemodialysis in relation to the dose in the objective function value by a further 24.1 points.
(up to 4 hours delayed) and also variability regard- The CLCR indicator variable explained 35% of the
ing the duration of the infusion (15-60 minutes). between-subject variance in CLNHD and also reduced
A postdialysis dosing schedule was simulated, giv- the between-subject variance in Vd by 53% (see Table II
ing 3 commonly used postdialysis doses (160 mg as for parameter values with different models).
the first dose and 120 mg as the second and third dose) Including weight or ideal body weight into the
within 4 hours after the termination of each dialysis model alone or combined as influential factors on
session every 48 hours. Consequently, success rates Vd or CLNHD did not improve model fit. An attempt
were compared between the proposed best dosing reg- was made to include fluctuations in extracellular
imen and the empirical (postdialysis) dosing schedule. fluid volume as a function of the changing wet
weight as a covariate for the Vd, but the data did not
RESULTS support this.
The final model contained HD as a covariate for
Forty-six patients were included in the NONMEM CLHD and centered CLCR as a covariate for CLNHD.
analysis, 20 were enrolled prospectively, and 26 The mean value of interdialytic gentamicin clear-
patients were enrolled retrospectively. The patients’ ance was 0.453 L/h, and the mean value for gentam-
ages ranged from 18 to 83 years, with a mean of 57.3 icin clearance during dialysis was 4.69 L/h. The

1262 • J Clin Pharmacol 2006;46:1259-1267

 GENTAMICIN IN PATIENTS WITH ESRD RECEIVING HEMODIALYSIS

Table II Parameter Values Estimated With the Base, Base Hemodialysis (HD),
and Final Covariate Model
Parameter Base Model Base HD Model Final Model (SE%)

CL, L/h 0.604 — —

CLNHD, L/h — 0.388 0.453 × CLCR/0.53 (0.9)
CLHD — 4.74 4.69 (0.86)
V, L 22.5 24.3 23.5 (0.91)
*ΩCL 0.271 0.406 0.264 (0.59)
*ΩV 0.0637 0.0537 0.0256 (0.45)
Σ proportional** 0.133 0.0625 0.0804 (1.77)
additive** 3.54 ×10–10 0.0495 0.00659 (3.05)
CL, clearance; CLNHD, nonhemodialysis clearance; CLHD, clearance during hemodialysis; Vd, volume of distribution; *Ω refers to the lognormal variance
of η (measure for BSV) corresponding to CLNHD (CL base model) and Vd. **variance.

observed versus predicted concentrations for the base

A and final model are shown in Figure 1.
Of the study patients, 38 had postdialysis dosing
14
and an evaluable peak concentration taken. The
Observed concentrations(DV)

12 remaining patients who had postdialysis dosing did

not have a blood sample taken near (within 30 min-
10
utes of) the actual time of the Cmax (see Figure 2 for the
8 distribution of observed “Cmax” values). Four patients
6
(11% of these patients) attained a peak concentra-
tion ≥8 mg/L, and 2 of these patients had an AUC
4 above the maximum target of 240 mg·h/L/48 h. Both
2 patients had estimated values of CLNHD and CLCR lower
than the average values for the population, and the
0 administered doses were 120 mg and 180 mg post-
0 2 4 6 8 10 12 dialysis. Only one patient received predialysis dosing
Predicted concentrations (specifically 240 mg gentamicin immediately before
dialysis), and this patient achieved an observed peak
concentration of 8.5 mg/L, and an AUC of 89.6 mg·h/L.
B
Only 4 patients in the study had AUC values above the
14 maximum target. Thirty-four patients had low values of
the observed “Cmax” values of between 2 and 7 mg/L.
Observed concentrations(DV)

12

10 Dose Individualization

8 Multiple dosing schedules were evaluated based on

6
the final covariate model. The best dosing schedule
identified for gentamicin through the simulations
4 was 300 mg as a first dose, 240 mg as a second dose,
and 220 mg as a third dose, immediately before
2
hemodialysis occurring every 48 hours, with up to 4
0 hours flexibility between the dose and hemodialy-
0 2 4 6 8 10 sis. This dosing schedule achieved treatment success
Predicted concentrations for all 3 criteria for all 3 doses in 23.4% of patients
and resulted in a satisfactory peak concentration in
Figure 1. Observed versus population predicted concentration more than 90% of patients for all 3 doses, with 85%
for (A) base model and (B) final model. of patients achieving a maximum value of AUC

PHARMACOKINETICS 1263

Figure 2. Observed peak concentrations with postdialysis dos-
ing (n = 38).
(AUCmax) below 240 mg·h/L at all times through
the 6-day course of treatment (see Table III and
Figure 3).
None of the simulated patients receiving the post-
dialysis dosing schedule (160 mg, 120 mg, and 120 mg
as first, second, and third dose, respectively) achieved
overall success, and the main reason for this was the
low peak concentrations achieved with this dosing
regimen (see Table III). This regimen was better at
meeting the AUC criteria than the peak concentration
criterion; thus, unacceptable aminoglycoside expo-
sure appears to be relatively infrequent with this dos-
ing schedule.
It is worth noting that although we provide dosing
suggestions for up to 3 days postdose that these doses
would need to be adjusted to meet the patient’s
pharmacokinetic and clinical needs. We include the
doses to highlight 2 points, to show that (1) doses
when given predialysis are larger (almost twice the
dose) and that (2) minimal accumulation occurs when
dosing is given predialysis. This latter point is shown
as the second and subsequent doses are not greatly
Table III Percentage of Success Rate Achieved With the Simulated Dosing Schedules
Criteria Cmax ≥ 8 mg/L
Predialysis dosing
1. 300 mg 97
2. 240 mg 97
3. 220 mg 91
Postdialysis dosing
1. 160 mg 0 89
2. 120 mg 0.7
3. 120 mg 6.1
Cmax, maximum concentration; AUCmin, minimum value of the area under the concentration time curve; AUCmax, maximum value of the area under the
concentration time curve.
1264 • J Clin Pharmacol 2006;46:1259-1267
TEIGEN ET AL
reduced from that of the first dose when the doses
are administered predialysis.
DISCUSSION
The model developed in this study describes the phar-
macokinetics of gentamicin in hemodialysis patients
and was used to explore dosing regimens aiming to
improve the efficacy-toxicity profile when adminis-
tered to patients with ESRD receiving hemodialysis.
Although it appears to be common practice to
dose aminoglycosides after patients have received
hemodialysis, simulations from the model indicate
that attainment of suitable peak concentrations is
very poor in this circumstance. However, it appears
that these regimens may provide a suitable exposure
level. Simulations of a postdialysis dose of gentam-
icin of 160 mg yielded no patients who attained a
Cmax greater than 8 mg/L on the first dose. This dose
however provided a reasonable distribution of AUC
values, which suggests that doses that will provide
appropriate Cmax values are likely to result in over-
exposure. The only dose from which a small fraction
of patients actually met the peak concentration treat-
ment criterion was for the third dose and essen-
tially arose because of significant accumulation that
occurred over the 3 dose periods. Whenever doses
lower than the 160 mg/120 mg/120 mg scenario are
administered, even poorer results may be anticipated
in terms of efficacy than with the simulated post-
dialysis regimen.
The estimated value of gentamicin clearance dur-
ing dialysis (4.7 L/h) is similar to values of clearance
observed in patients with normal renal function.28 In
addition, in our study we found a 51% BSV in gen-
tamicin clearance, which is comparable to 45% for
Success in All
AUCmin AUCmax Criteria on All Doses
≥ 140 mg·h/L/48h ≤240 mg·h/L/48h (overall success)
77 92 23
75 85
70 89
93 0
84 77
82 76
 GENTAMICIN IN PATIENTS WITH ESRD RECEIVING HEMODIALYSIS

function and weighing 72.4 kg (the mean value in

A this study population), an elimination half-life of 2.5
Cmax 1. dose predialysis Cmax 2. dose predialysis hours would be expected, which relates to a clear-
dosing dosing
250 250 ance in such a patient to be approximately 5 L/h. Xuan
200 200 et al recently found a gentamicin clearance of 4.32
150 150
L/h in a pharmacokinetic evaluation of 939 adult
100 100
hospitalized patients on aminoglycoside therapy.31
50 50
Thus, hemodialysis appears to offer almost normal
clearance conditions in patients with ESRD during
0 0
6 8 10 12 14 6 8 10 12 14 the dialysis period. In essence therefore, the dialy-
Cmax 3. dose predialysis
sis period will provide the most close to “normal”
300
dosing pharmacokinetic-pharmacodynamic profile for gen-
250
tamicin in patients with ESRD. From this study, for
200 a typical 4-hour hemodialysis session, the clearance
150 of gentamicin during dialysis (18.8 L/4 h) is approx-
100 imately equivalent to the average total clearance dur-
50 ing the interdialytic interval (19.9 L/44 h).
0
6 8 10 12 14 16
Based on predialysis dosing simulations from this
study, it was found that an appropriate dosing strategy
of gentamicin for patients who dialyze 3 times a week
B to be 300 mg predialysis as the first dose and then sub-
AUC 1. dose predialysis AUC 2. dose predialysis
sequent predialysis doses of 240 mg and 220 mg as
dosing dosing second and third dose, respectively. This regimen pro-
250 250 duced a desirable peak concentration (above 8 mg/L)
200 200 in 97% of patients for the first and second dose and a
150 150 91% success for patients for the third dose without
100 100 unacceptably high exposure (see Table III). This illus-
50 50
trates how higher doses (300 mg, 240 mg, 220 mg)
can be administered predialysis, because of the subse-
0 0
0 100 200 300 400 0 100 200 300 400 500 quent clearance provided by dialysis (similar to
gentamicin clearance in patients with normal renal
AUC 3. dose predialysis
dosing
function), resulting in a lower total exposure than
300 when administering lower doses (160 mg, 120 mg, 120
250 mg) postdialysis. The doses discussed here are only
200 starting conditions, and it is recommended to monitor
150
gentamicin concentrations from the first dose and
100
adjust the dose accordingly using Bayesian dose indi-
50
vidualization methodology in conjunction with knowl-
0
0 100 200 300 400 500
edge of the patient’s current clinical picture. It should
also be noted that the optimal exposure levels have yet
to be determined for this patient population, and it has
Figure 3. Histogram of the simulated criteria values compared been assumed in this study that exposure levels for
to target values (vertical lines) for predialysis dosing for (A) max-
imum concentration (Cmax) and (B) area under the concentration- patients with some level of intact renal function are a
time curve (AUC) for a dose of 300 mg for the first dose, 240 mg reasonable surrogate for those with ESRD.
for the second dose, and 220 mg for the third dose. The final model included the indicator for residual
renal function, provided by CLCR, as a covariate, and
this was the only covariate that improved model fit.
patients with normal renal function.28 In 2 other stud- Creatinine clearance as a measure for residual renal
ies evaluating dialyzer membranes with increased function is expected to be less accurate in hemodial-
permeability (high-flux membranes), only moderately ysis patients compared to patients with normal renal
higher values than this (5.5 L/h and 7 L/h) are reported, function or less advanced renal impairment.25 In
corresponding to a half-life of 2.2 hours or more during hemodialysis patients, plasma creatinine is a reflection
dialysis.29,30 In a typical patient with normal renal of dialysis adequacy and the amount of body muscle,

PHARMACOKINETICS 1265
 TEIGEN ET AL

as well as residual renal function. In addition, tubu- We wish to acknowledge assistance from medical and nursing
lar secretion of creatinine may contribute to an over- staff in the hemodialysis units, pathology, and pharmacy depart-
ments at Princess Alexandra Hospital through the course of the
estimation of glomerular filtration, which may be
study.
more significant as renal dysfunction progresses.25-27
The observed range for the estimated CLCR in this Financial disclosure: We also wish to acknowledge the University
study is high (range, 0.27-1.24 L/h; mean, 0.53 L/h). of Queensland for financial support through an ECR Grant (2003).
It is likely that estimation of CLCR by urine collection
would have resulted in lower values, as urine pro- APPENDIX
duction in a considerable proportion of patients is Filter Types Used for Patients in This Study
often minimal. Nevertheless, the covariate CLCR was
a clinically and statistically significant predictor of Filter Type Number of Patients
interdialytic gentamicin clearance. The variation in
CLCR explained a substantial amount of the observed Fresenius F10 HPS Low Flux 2.4 11
Fresenius F7 HPS Low Flux 1.6 3
variability in clearance between dialysis sessions.
Fresenius F7 Low Flux 1.6 1
Whether CLCR in this setting is predominantly a Fresenius F8 HPS Low Flux 1.8 3
characterization of creatine producing body mass or Fresenius F8 Low Flux 1.8 1
some level of residual renal function is unknown. Fresenius FX80 2
Caution should be taken if this relationship is extrap- Fresenius FX80 S 1.8 3
olated to other types of dialysis settings. Fresenius HF80 1.8 10
The developed model in this study was empirically Fresenius HF80 S 1.8 1
based (although has reasonable biological grounds) Gambro Allwal GFS/GEH Plus 11 1
and included a switch that turned clearance due to (Haemophan)
dialysis on and off according to onset and offset Gambro Polyflux 140 H 3
times of hemodialysis. A semimechanistic model Gambro Polyflux 170H 5
Gambro Polyflux 210H 2
that was developed previously,19 which accounts for
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