ORIGINAL RESEARCH ARTICLE

Clin Pharmacokinet 2005; 44 (5): 495-507

0312-5963/05/0005-0495/$34.95/0
2005 Adis Data Information BV. All rights reserved.

Pharmacokinetic Profile of
Ganciclovir After its Oral
Administration and From its Prodrug,
Valganciclovir, in Solid Organ
Transplant Recipients
Hugh Wiltshire,1 Sarapee Hirankarn,2 Colm Farrell,2 Carlos Paya,3 Mark D. Pescovitz,4
Atul Humar,5 Edward Dominguez,6 Kenneth Washburn,7 Emily Blumberg,8
Barbara Alexander,9 Richard Freeman,10 Nigel Heaton11 and The Valganciclovir Solid
Organ Transplant Study Group
1
2
3
4
5
6
7
8
9
10
11

Roche Products Ltd, Welwyn Garden City, UK

GloboMax a division of ICON plc., Marlow, UK
Mayo Clinic, Rochester, New York, USA
Departments of Surgery/Microbiology/Immunology, Indiana University, Indianapolis,
Indiana, USA
Toronto General Hospital, Toronto, Ontario, Canada
University of Nebraska Medical Center, Omaha, Nebraska, USA
University of Texas Health Science Center, San Antonio, Texas, USA
Hospital of the University of Pennsylvania, Philadelphia, Pennsylvannia, USA
Duke University Medical Center, Durham, North Carolina, USA
New England Medical Center, Boston, Massachusetts, USA
Kings College, London, UK

Abstract

Background: Valganciclovir (Valcyte) has recently been approved for the

prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negative [R]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients
are lacking. A recent randomised, double-blind study of valganciclovir in
364 D+/R (intent-to-treat population) SOT recipients provided valuable data on
which a population pharmacokinetic analysis was performed.
Methods: The pharmacokinetics of ganciclovir from oral ganciclovir
(Cymevene, 1000mg three times daily) and from valganciclovir (900mg once
daily) were described with plasma levels from 240 patients (1181 datapoints
describing 449 pharmacokinetic profiles) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment pharmacokinetic model with
separate absorption/metabolism and absorption parameters for valganciclovir and
ganciclovir, respectively, was developed.
Results: Exposure to ganciclovir from valganciclovir averaged 1.65-fold greater
than that from oral ganciclovir (95% CI 1.58, 1.81); respective daily area

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Wiltshire et al.

under the plasma concentration-time curve values were 46.3 15.2 g h/mL and
28.0 10.9 g h/mL. The relative systemic exposure of ganciclovir was approximately 8-fold higher from valganciclovir than oral ganciclovir. Exposure to
ganciclovir from valganciclovir was similar among liver, heart and kidney transplant recipients (46.0 16.1, 40.2 11.8 and 48.2 14.6 g h/ mL, respectively). Adherence to the prescribed dosing regimens, which were reduced for renal
impairment, gave consistent exposure to ganciclovir.
Conclusion: Oral valganciclovir produces exposures of ganciclovir exceeding
those attained with oral ganciclovir, but in line with those reported after standard
intravenous administration of ganciclovir. This indicates that oral valganciclovir
is suitable in circumstances requiring prophylactic use of ganciclovir and allows
for more convenient management of patients at risk of CMV disease.

Background
Cytomegalovirus (CMV) is the most common
viral infection following solid organ transplantation
(SOT)[1] and is a significant cause of morbidity and
mortality, especially in high-risk individuals (i.e.
CMV seronegative recipients [R] of an organ from
a CMV seropositive donor [D+]).[2]
The efficacy and safety of intravenous[3,4] and
oral ganciclovir (Cymevene 1, F. Hoffmann-La
Roche Ltd, Basel, Switzerland)[5,6] in the prevention
of CMV disease in SOT recipients have been well
documented; however, there are a number of limitations with both these formulations. Administration
of intravenous ganciclovir is associated with patient
inconvenience, high cost and a high incidence of
catheter-related infections.[7] On the other hand, oral
ganciclovir has low bioavailability, which limits
achievable systemic exposure;[5] to deliver plasma
ganciclovir exposure 4050% of that achieved with
intravenous ganciclovir 5 mg/kg (generally considered the gold standard), 3000mg of oral ganciclovir, administered as 12 capsules/day in a threetimes-daily regimen must be administered.[8,9]
Valganciclovir (Valcyte, F. Hoffmann-La
Roche Ltd, Basel, Switzerland), a prodrug ester of
ganciclovir and L-valine, has recently been developed to overcome these limitations. It is well absorbed from the gastrointestinal tract and rapidly
metabolised in the intestinal wall and liver to
1

ganciclovir. Following absorption, the major route

for clearance of ganciclovir is renal excretion of the
unchanged compound.[10] In liver transplant patients, the systemic exposure of ganciclovir from
valganciclovir is approximately 60% relative to intravenous ganciclovir, which is considerably greater
than that of orally administered ganciclovir.[9] Similar average systemic exposure values for ganciclovir
from valganciclovir have been obtained in healthy
and HIV-infected subjects (59%) and AIDS patients
(59% with once-daily administration and 64% with
twice-daily administration).[11,12] Valganciclovir
900mg provides systemic exposure to ganciclovir
similar to that from intravenous ganciclovir 5 mg/
kg/day.[13,14]
Recently, a large randomised, double-blind study
was conducted to evaluate the efficacy and safety of
valganciclovir 900mg once daily compared with
oral ganciclovir 1000mg three times daily for the
prevention of CMV disease in high-risk D+/R SOT
patients.[15] As part of this study, blood samples
were collected for pharmacokinetic analysis. Furthermore, as ganciclovir is cleared renally, doses for
patients with renal impairment (creatinine clearance
[CLCR] <60 mL/min) were adjusted according to a
dose-reduction algorithm (see table I). The objectives of the current study were to determine: (i) the
most appropriate models to describe the pharmacokinetics of ganciclovir from valganciclovir and
oral ganciclovir; (ii) the relative systemic exposure

The use of trade names is for product identification purposes only and does not imply endorsement.

2005 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2005; 44 (5)

Valganciclovir/Ganciclovir in Transplant Patients

497

Table I. Descriptive statistics of area under the plasma concentration-time curve from 0 to 24 hours (AUC24) from the valganciclovir
pharmacokinetic model
Variable

All doses

No. of subjects

160

No. of profiles

298

Mean AUC24 [g h/mL] (SD)

CLCR = creatinine clearance.

46.34 (15.22)

225 mg/day
(CLCR 2540 mL/min)

450 mg/day
(CLCR 4060 mL/min)

900 mg/day
(CLCR >60 mL/min)

52

128

74

216

22.61 (4.20)

to ganciclovir from oral ganciclovir and valganciclovir; (iii) a comparison of exposure to

ganciclovir in liver, heart and kidney recipients; and
(iv) the effectiveness of the dose-reduction algorithm in preventing over- and under-exposure to
ganciclovir in renally impaired patients.
Patients and Methods
This study was based on a subset of patients
taken from a double-blind, double-dummy trial that
has recently been published.[15] In brief, patients
(n = 364) [intent-to-treat population] were 13 years
of age and received a first heart, liver, kidney,
kidney-pancreas, kidney-heart or kidney-liver allograft, or a second kidney allograft, with a CMV
serostatus of D+/R. Patients were excluded if they
had a history of CMV infection or disease, antiCMV therapy within the previous 30 days, severe,
uncontrolled diarrhoea or other evidence of malabsorption.
Patients were randomly assigned in a 2 : 1 ratio
to receive valganciclovir 900mg once daily or oral
ganciclovir 1000mg three times daily. In patients
with impaired renal function, the dose was adjusted
according to estimated CLCR (table I).[11] Treatment
began within 10 days post-transplant (as soon as the
patient was able to take oral medication) and continued through to day 100 post-transplant.
Sampling and Assay of Ganciclovir

Plasma levels of ganciclovir were scheduled to

be measured on two occasions 6 weeks apart, the
first at least 28 days post-transplant. In 61% of
patients, the three post-dose samples that covered
the absorption (13 hours), distribution (512 hours)
and elimination (2224 hours) phases were taken on
both occasions. Patients were defined as evaluable
2005 Adis Data Information BV. All rights reserved.

38.57 (11.05)

49.88 (14.95)

for pharmacokinetic analysis if they had at least two

usable samples on one occasion. No attempts to
analyse valganciclovir plasma levels were made as
previous studies have shown that post-administration valganciclovir plasma concentrations are very
low.[9,11]
Venous blood (5mL) was drawn into ethylene
diamine tetraacetic acid (EDTA) Vacutainer tubes
and placed on ice until centrifugation (15 minutes at
2000 rpm) at 4C within 30 minutes of blood collection. Plasma samples were frozen immediately at
20C until analysis. Concentrations of ganciclovir
were determined using high-performance liquid
chromatography with fluorescence detection.[16]
This method has a validated range of 0.044.00
g/mL. In this study, the precision of the ganciclovir
assay from quality control samples was 4.67.8%,
and the accuracy was 99104%.
Pharmacokinetic Analysis

The pharmacokinetics of ganciclovir after administration of oral ganciclovir or valganciclovir

were analysed using the population approach and
the nonlinear mixed-effects modelling (NONMEM)
software.[17] The first-order conditional estimation
method with interaction was used.
Model Development

An initial structural model of the pharmacokinetics of ganciclovir after administration of valganciclovir was created from rich historical
data.[9,11] A two-compartment model was selected,
as the pharmacokinetic curves of ganciclovir after
intravenous administration are biphasic. CLCR was
used as a predictor of renal function and, therefore,
clearance of ganciclovir.
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Wiltshire et al.

The model was parameterised in terms of apparent clearance, apparent central volume of distribution, intercompartment clearance, apparent peripheral volume of distribution and lag-time. Interindividual variability in the rate of absorption,
apparent clearance and central volume of distribution was assessed using an exponential error model
as illustrated by the following equations:
Rate of absorption (equation 1):
KAj = KA exp(jKA)
jKA i.i.d ~ N(0,2KA)
(Eq. 1)
where KA is the typical population value of the
absorption rate constant; jKA represents the difference between the jth individuals KA values and the
predicted value; jKA values are independent, identically distrubuted (i.i.d.) random variables; N(0,2)
means normally distributed about 0 with variance
2; and j is the variable for the jth individual.
Apparent clearance (equation 2):
CLj = CL exp(jCL)
jCL i.i.d ~ N(0,2CL)
CL = 1 [CLCR/median]2

(Eq. 2)
where 1 and 2 are the parameters estimated by the
model; CL is the typical population value of clearance; and median is the median CLCR of the population.
Central volume of distribution (equation 3):
V2j = V2 exp(jV2)
jV2 i.i.d ~ N(0,2V2)
(Eq. 3)
where V2 is the central volume of distribution and j
is the variable for the jth individual.
A combined additive and exponential model was
used for the residual random effects. Modelling of
interoccasion variability was performed on both apparent clearance and central volume of distribution.
The dataset for valganciclovir was divided into
two subsets: (i) the modelling dataset, which comprised data from the first two-thirds of the patients in
enrolment order; and (ii) the validation dataset,
2005 Adis Data Information BV. All rights reserved.

which comprised data from the last one-third of the

patients who were enrolled. Modelling was initiated
using draft data while the study was ongoing. Personnel at GloboMax, Marlow, UK, who carried out
the modelling were unblinded, while personnel at
the sponsor site (Roche, Welwyn, UK) remained
blinded.
The modelling dataset from the draft data was
used to derive the basic pharmacokinetic model, to
select primary covariates (namely bodyweight,
CLCR, transplant type) and to model any potential
time dependence. Model qualification was performed using the validation dataset from the final
data. The final data of all patients in the valganciclovir arm were used to evaluate the influence of
secondary covariates (race, sex, time since transplantation, country/continent and concomitant immunosuppressive regimen [ciclosporin, tacrolimus,
mycophenolate mofetil and azathioprine]) and to
derive the final pharmacokinetic model.
The final model after valganciclovir administration was applied to the pharmacokinetic data from
the ganciclovir arm of the study and the predictability of the model was assessed. Subsequently, a combined model was applied to the ganciclovir data
from the valganciclovir and ganciclovir arms. A
two-compartment model with two different firstorder absorption (plus metabolism for valganciclovir) rates and lag-times were used for the valganciclovir and ganciclovir arms of the study. There
were twice as many patients in the valganciclovir
group than the ganciclovir group, and a simpler
administration regimen (once daily rather than three
times daily). The model-development and covariate
analysis were, therefore, applied to this dataset
before any attempts were made to model the data
from oral ganciclovir treatment. The absorption
rates and lag-times were fixed to results obtained by
modelling rich data.[9,11] As there were no data after
intravenous administration of ganciclovir, the
bioavailability of ganciclovir from valganciclovir
was set to unity and apparent volumes and clearances were calculated. The base model included
estimated CLCR as a predictor of the clearance of
ganciclovir.
Clin Pharmacokinet 2005; 44 (5)

Valganciclovir/Ganciclovir in Transplant Patients

Pharmacokinetic Model Assessment

The model was assessed according to goodnessof-fit[18] and NONMEM objective function value
(OFV).[19]
Covariate Analysis

The effect of potential covariates on the pharmacokinetic parameters was modelled separately for
each selected pharmacokinetic parameter. Each
covariate was modelled as a multiplicative effect of
the covariate raised to an estimated power. For all
continuous covariates, the covariate effect was centred on the median of the covariate. Categorical
covariates with more than two categories were
analysed as a multiple of the component binary
variables. Binary covariates were normalised to values >0 and a geometric mean of unity.
Selection of Covariates

The significance of including or removing fixed

effects into the population model was evaluated by
the Likelihood Ratio Test, using forward and backward selection processes with a priori levels of
0.05 and 0.01, respectively. During forward selection, the effect of each covariate on each basic
pharmacokinetic parameter was added to the model.
All fixed effects except the coefficient for the power
of the covariate were held constant. The effect causing the largest reduction in the OFV was considered
to be the most significant and was added to the
model if the reduction exceeded 3.841. All the parameters of the new refined model were estimated
and the selection process was repeated until no
further covariate could be selected. This was the
full model.
The importance of each covariate was re-evaluated by backward selection, eliminating each
covariate from the full model, one at a time and
separately for each pharmacokinetic parameter. The
covariate with the smallest increase in the OFV was
excluded if the increase was <6.635 and no substantial increase occurred in the corresponding random
effect parameter. The exclusion of covariates was
continued as long as a covariate fulfilled the exclu 2005 Adis Data Information BV. All rights reserved.

499

sion criteria. The resulting model was called the

final population pharmacokinetic model. The OFV
from each model was tabulated to document the
process of model development.
Clinical Relevance

The clinical relevance of the effect of a selected

covariate on the corresponding pharmacokinetic parameter was evaluated according to the following
criteria and only covariates with clinically relevant
effects were included in the final model. For a
binary covariate (e.g. sex), a clinically relevant effect was defined as a change in the typical (population) pharmacokinetic value from the lower to the
higher value of at least 25%. A continuous covariate
(e.g. CLCR) was considered clinically relevant if its
inclusion caused at least 10% of the patients in the
dataset to have an individual typical pharmacokinetic value outside the range of 80125% of the typical
value of the pharmacokinetic parameter without the
covariate.
Model Qualification

Model validation was based on both the observed

concentrations and on the derived pharmacokinetic
parameters. The pharmacokinetic model and parameter estimates obtained from the modelling dataset
were used to predict the ganciclovir concentrations
and pharmacokinetic parameters for those patients
in the validation set, using their dosing and sampling
information and the relevant covariate data. The
predicted plasma concentrations were then compared with the observed concentrations. The mean
difference between observed and model-predicted
concentrations (bias), mean-square error of the difference (MSE) and percentage prediction error (PE)
were used as predictive performance criteria.
The pharmacokinetic model from the modelling
dataset was fitted to the data from the validation
dataset to obtain estimates for the individual pharmacokinetic parameters. These parameters were
compared with the predicted pharmacokinetic parameters. Bias, MSE and PE were also calculated to
evaluate the deviation.
Clin Pharmacokinet 2005; 44 (5)

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Wiltshire et al.

Results
A total of 240 patients (valganciclovir, n = 160;
ganciclovir, n = 80) provided suitable plasma samples. The demographics, baseline characteristics and
distributions of transplant organ types between the
overall patient population and the pharmacokinetic
population were comparable.[15]
Base Model Development

As mentioned earlier the initial pharmacokinetic

model was developed using rich historical data.[9,11]
A complex model with two first-order parallel
processes, conceptually corresponding to the absorption and hydrolysis of valganciclovir in the gut
wall and liver, described the data better than the
simple first-order appearance of ganciclovir in plasma. The population-mean apparent central volume
of distribution of ganciclovir derived from the complex absorption model (30.9L) was approximately
34% higher than that from a simple absorption
model (23.1L). Apparent clearance was similar in
the two models (15.1 L/h vs 15.7 L/h).
Application of these models to the sparse data
from this study was generally more satisfactory
when the absorption parameters were fixed to those
from the historical studies, rather than being esti-

mated. Although the complex absorption model

generated a lower OFV, the difference was relatively small compared with that from the modelling of
the rich historical data. In addition, the complex
model was unstable in that covariance matrices were
not obtained and the 30-fold longer run time required for minimisation meant that the simple model
was used for the covariate analysis and definitive
parameter estimates.
Pharmacokinetic Model After Oral
Administration of Valganciclovir

Prior to the primary covariate analysis, the influence of CLCR on ganciclovir clearance, which was
included a priori, was removed from the base
model. Using the modelling dataset, the most significant primary covariate was found to be CLCR on
ganciclovir clearance. Thus, after deletion of some
potential outlying samples, the inclusion of CLCR as
a predictor of ganciclovir clearance reduced the
OFV from 580.1 to 482.2. The relationship between
bodyweight and central volume of distribution was
also found to be significant (OFV = 471.2). No
significant reduction in OFV followed the introduction of interoccasion variability.
The influence of secondary covariates (race, sex,
time since transplantation, country/continent and

Table II. Demographic data for the validation dataset for the valganciclovir model
Variable

All

Liver transplant

Heart transplant

Kidney and kidneypancreas transplant

Sex
male
female
Age (y)a

37

21

0
40.8 (15.6)

10
3

43.8 (13.5)

46.5 (11.4)

39.7 (15.3)

Height (cm)a

172.9 (12.6)

175.2 (10.9)

176.6 (4.6)

166.6 (15.9)

Weight (kg)a

79.6 (21.2)

83.8 (18.7)

74.7 (8.5)

73.6 (27.8)

Creatinine clearance (mL/min)a

91.4 (35.6)

99.3 (35.0)

97.1 (35.8)

73.1 (30.8)

Race
Caucasian

43

25

Black

other

12
1

Continent
Europe
North America
Australia/Oceania
a

37

20

13

Values are mean (standard deviation).

2005 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2005; 44 (5)

Valganciclovir/Ganciclovir in Transplant Patients

immunosuppressive
regimen
[ciclosporin,
tacrolimus, mycophenolate mofetil and azathioprine]) was assessed using the final data from all
patients in the valganciclovir arm. A total of 810
plasma concentrations were included in the final
valganciclovir dataset that followed the deletion of
40 outlying samples, which were excluded as they
were considered implausible (weighted residuals
generally >6); a further 11 samples were below the
limit of quantification. Using this reduced dataset,
the next most significant covariate was sex on central volume of distribution (OFV reduced from
552.7 to 541.9). Sex was also clinically significant
since the change in the typical central volume of
distribution from male to female was 58.8%. In the
second selection step, tacrolimus dose was the most
significant covariate. However, although covariate
analysis indicated that tacrolimus was associated
with significantly increased clearance of ganciclovir
(OFV decreased by 21), this effect was not considered clinically significant as no individual typical
clearance was outside 80125% of the typical value
of the model with the covariate excluded. There
were no further significant covariates. The full
covariate model, therefore, included CLCR and
bodyweight as primary covariates and sex as a secondary covariate.
Evaluation of various diagnostic tests (comparison of observed and predicted plasma levels, residual plots) on the final valganciclovir model showed
that it predicted the observed plasma concentrations
of ganciclovir well and that the resultant estimated
area under the plasma concentration-time curve
(AUC) values were reliable (table I). The model
(developed with two-thirds of the study data) was
validated by application of the final one-third of the
data (validation dataset). Demographic details of the
validation dataset from the valganciclovir model are
presented in table II. The model was shown to be
robust by the small bias between the observed and
predicted concentrations (table III), apparent clearance and central volume of distribution and by the
similarity of results with, and without, parameter
estimation. The pharmacokinetic parameters in the
final model were all estimated precisely with rela 2005 Adis Data Information BV. All rights reserved.

501

Table III. Performance of the valganciclovir pharmacokinetic model

in estimating apparent clearance and central volume of distribution
Apparent clearance
(L/h) [n = 80]

Central volume of
distribution (L) [n = 80]

0.49 0.57
3.33

0.78 2.57
14.41

Bias
mean SD
min
max

0.35

2.87

MSE
mean SD

0.57 1.39

7.11 28.70

min

3.6 105

1.85 103

max

11.10

207.59

PE
mean SD

3.44 2.85

6.57 6.65

min

0.09

0.29

max
17.68
40.39
Bias = mean difference between observed and model-predicted
concentrations; max = maximum; min = minimum; MSE = meansquare error of the difference; n = number of pharmacokinetic
profiles; PE = percentage prediction error.

tive standard errors of <20% and the residual error

was 38.6%.
Pharmacokinetic Model After Oral
Administration of Ganciclovir

The same two-compartment model with firstorder absorption was applied to the pharmacokinetics of oral ganciclovir, but employed the absorption
values previously estimated for oral ganciclovir
1000mg three times daily.[9] However, because of
the smaller number of patients receiving oral
ganciclovir and the fact that oral ganciclovir was
given three times daily rather than once daily, the
precision of many of the parameters was poor.
Combined Pharmacokinetic Model After
Oral Administration of Ganciclovir
or Valganciclovir

In order to improve the modelling of the distribution and elimination phases of ganciclovir, the
ganciclovir and valganciclovir datasets were combined and a relative systemic exposure parameter
introduced. After the omission of 6/417 (1.5%) clear
outliers (weighted residuals >7) from the ganciclovir data, a satisfactory fit was obtained. As with
the valganciclovir model, the basic combined model
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Wiltshire et al.

Table IV. Final parameters of the combined pharmacokinetic model for ganciclovir delivered by oral ganciclovir and valganciclovir
Parameter

Final estimate

RSE (%)

95% CI
0.282, 0.437

Absorption/metabolism rate constant (h1) [valganciclovir]

0.36

11.0

Lag-time (h) [valganciclovir]

0.661

Fixed

Absorption rate constant (h1) [ganciclovir]

0.128

10.4

Lag-time (h) [ganciclovir]

0.883

Fixed

Relative systemic exposure

0.134

Central volume of distribution (L)

25.0

Peripheral volume of distribution (L)

49.0

Inter-tissue clearance (L/h)

12.0

Systemic clearance (L/h)

12.4

Power for creatinine clearance on systemic clearance

Power for bodyweight on systemic clearance
Power for sex on central volume of distribution
Power for tacrolimus on clearance

0.925
0.725
0.530
0.172

Mean values
RSE
RSE = residual standard error.

5.76
20.4

RSE (%)

0.121, 0.146

28.3

14.5

19.2, 30.8

64.2

35.1

0.101, 0.154

43.4, 54.6
7.17, 16.8

2.48

11.8, 13.0

4.91

0.835, 1.010

17.1
17.2
3.55

18.2

7.94

0.480, 0.969
0.350, 0.710
0.159, 0.184

9.92

36.9

19.2

35.6%

fixed the absorption rates and lag-times to previously observed values (different for the two compounds) and used CLCR as a predictor of apparent
clearance, and bodyweight as a predictor of central
volume of distribution. In addition, subject variability terms for both apparent clearance and for central
volume of distribution were included.
The possible effect of organ transplant type on
the primary pharmacokinetic parameters (apparent
clearance and central volume of distribution) was
investigated by covariate analysis. No statistically
significant effect was seen, as the reduction in OFV
was <3.841 in every case. As with the valganciclovir
model, introduction of sex as a predictor of central
volume of distribution was statistically significant,
with both the OFV and the intersubject variability
being reduced. The population-mean central volume
of distribution of ganciclovir was estimated to be
56% lower in females than males. This was in
addition to females being lighter.
The median CLCR in males (80.4 mL/min) was
22% higher than in females (65.8 mL/min), but the
dose reduction algorithm corrected for this and the
median systemic exposure was only 5% less. The
impact of interindividual variability on relative systemic exposure (OFV decreased by 14), bodyweight
on peripheral (rather than central) volume (OFV
2005 Adis Data Information BV. All rights reserved.

4.56
11.8

Intersubject
variability (%)

decreased by 34) and estimation of the absorption

rates for ganciclovir (OFV decreased by 100) and
then valganciclovir (OFV decreased by 7) were all
significant. No other immunosuppressive drug
coadministered with ganciclovir had a statistically
significant effect on apparent clearance or central
volume of distribution. The parameters of the final
population pharmacokinetic model are presented in
table IV.
Observed and Combined Model-Predicted
Ganciclovir Plasma Levels

Comparison of observed and model-predicted

plasma levels of ganciclovir after oral administration of valganciclovir or oral ganciclovir is shown in
figures 1a and 1b. Predicted concentrations were
less variable than those actually observed; however,
the sampling points adequately defined the overall
pharmacokinetic profiles of ganciclovir from valganciclovir.
Exposure to Ganciclovir

The AUCs from both valganciclovir and ganciclovir appeared to fit a log-normal distribution (figure 2). Exposure to ganciclovir from valganciclovir
averaged 1.65 times that from oral ganciclovir (95%
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Valganciclovir/Ganciclovir in Transplant Patients

503

CI 1.58, 1.81). Respective mean daily AUCs were

46.3 15.2 g h/mL (n = 298) and 28.0 10.9
g h/mL (n = 151). The ratio in liver, heart and
kidney transplants recipients was 1.85, 1.51 and
1.54, respectively. The relative systemic exposure of
valganciclovir was found to be 8.06 times that from
oral ganciclovir.

Exposure to ganciclovir from oral valganciclovir

was similar among recipients of liver (46.0 16.1
g h/mL), heart (40.2 11.8 g h/mL) and kidney (48.2 14.6 g h/mL) transplants (figure 3),
which indicated that the type of organ transplanted
had no influence on the pharmacokinetics of
ganciclovir.
Mean
Mean SD
Observed concentrations

a
100

10

Plasma concentration (ug/mL)

0.1

0.01
b

10

0.1

0.01
42

48

54

60

66

72

Time after dose administration (h)

Fig. 1. Comparison of observed and model-predicted plasma levels of ganciclovir after administration of: (a) oral valganciclovir 900mg once
daily; or (b) oral ganciclovir 1000mg three times daily in solid organ transplant recipients. Line graphs were simulated by Monte Carlo
analysis assuming a two-compartmental pharmacokinetic model with first-order absorption/formation rate constant of ganciclovir and lagtime with log-normal distributions of the variable parameters (clearance and central volume of distribution). The fixed parameters were those
used (absorption/formation rate constants and lag-times) or estimated (relative bioavailability, peripheral volume of distribution and intertissue clearance) in the nonlinear mixed-effects modelling (NONMEM) analyses. The mean and standard deviations of the natural
logarithms of the variable parameters were calculated for the post hoc estimated values and the simulations (n = 100) carried out for various
timepoints using ModelMaker software (Version 4, ModelKinetix, Oxford, UK).

2005 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2005; 44 (5)

504

Wiltshire et al.

Ganciclovir
Valganciclovir

16
14

Frequency

12
10
8
6
4
2
0
10 20 30 40 50 60 70 80 90 100 110 120
Systemic exposure (AUC24; g h/mL)
Fig. 2. Comparison of the distribution of the exposure of ganciclovir
after administration of oral valganciclovir 900mg once daily or oral
ganciclovir 1000mg three times daily in solid organ transplant recipients. AUC24 = area under the plasma concentration-time curve
from 0 to 24 hours; Frequency = number of patients in each AUC
group with defined exposure.

Adherence to the prescribed valganciclovir dosage regimen, adjusted for CLCR as described (table
I), gave consistent exposure, with 95% of patients
having a daily AUC of between 26 and 73 g h/mL
(figure 4). A number of patients received doses that
were not in accordance with the dosing algorithm
(16/298 overdosed and 28/298 underdosed). Exposure was within the predicted range for all patients
who were underdosed, but above predicted levels
for 9/16 overdosed patients. Except for one patient
with a borderline impaired CLCR (62 mL/min), all
the AUCs from those given valganciclovir according to the protocol were within the target limits.
Discussion
Intravenous ganciclovir has been the cornerstone
of the treatment and prevention of CMV disease in
SOT recipients;[20,21] however, more recently, oral
ganciclovir has been used. Although oral ganciclovir is effective in the prevention of CMV disease,[5,6,22] its low bioavailability (ranging from 6%
to 9%)[23] limits achievable systemic exposure.
Levels of ganciclovir in plasma higher than those
2005 Adis Data Information BV. All rights reserved.

achieved with oral ganciclovir may be required to

prevent CMV infection and disease in a significant
proportion of high-risk SOT recipients (i.e. D+/R).
The introduction of the oral prodrug valganciclovir as a potent anti-CMV drug is a significant advance in antiviral prophylaxis in transplant
recipients. Initial studies in HIV- and CMV-seropositive patients described the pharmacokinetic parameters of oral valganciclovir.[10,13] Valganciclovir
(aqueous solution 360mg once daily) was shown to
be rapidly and extensively hydrolysed to ganciclovir, which resulted in significantly greater relative systemic exposure (69%) than with oral
ganciclovir (1000mg once daily; 5.6%).[10]
Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are lacking. In this study, a structural model of the pharmacokinetics of ganciclovir after oral administration of
valganciclovir in SOT recipients was successfully
developed; however, application of this model to the
pharmacokinetics of ganciclovir after its oral administration was unsuccessful. There were only half the
number of patients in the ganciclovir arm compared
with the valganciclovir arm of this study and the
three-times-daily dosage regimen needed for ganciclovir was much harder to fit with the sparse data. In
order to improve the modelling of the distribution
and elimination phases, the ganciclovir and valganciclovir datasets were combined and a suitable
model was obtained.
Systemic exposure (AUC24; g h/mL)

18

120
100
80
60
40
20
0
Liver

Heart

Kidney

Fig. 3. Ganciclovir systemic exposure after administration of oral

valganciclovir 900mg once daily by organ transplant type. The medians are the lines in the middle of the boxes, whereas the tops and
bottoms are the 75th and 25th percentiles, respectively. The lower
and upper bars are the 10th and 90th percentiles, respectively, and
the circles are the outliers.

Clin Pharmacokinet 2005; 44 (5)

Valganciclovir/Ganciclovir in Transplant Patients

505

Dosage adjustment based on CLCR

Target range for dosing-algorithm

120

Correct dose
Underdose
Overdose

Systemic exposure (AUC24; g h/mL)

100

80

60

40

20

0
0

20

40

60

80

100

120

140

160

180

CLCR (mL/min)
Fig. 4. Relationship between ganciclovir exposure and creatinine clearance (CLCR) after administration of oral valganciclovir 900mg once
daily according to its dosing algorithm in solid organ transplant recipients.[11] AUC24 = area under the plasma concentration-time curve from
0 to 24 hours.

In the current study, valganciclovir 900mg once

daily produced steady-state plasma concentrations
of ganciclovir that were considerably higher than
those observed following administration of oral
ganciclovir at a dosage of 3000 mg/day. Average
exposure to ganciclovir from valganciclovir was
approximately 1.65 times (95% CI 1.58, 1.81) that
from oral ganciclovir (46.3 vs 28.0 g h/mL). Exposure to ganciclovir from valganciclovir was very
similar among liver, heart and kidney transplant
recipients.
The pharmacokinetics of ganciclovir from valganciclovir compared with oral and intravenous
ganciclovir have previously been described in a
small single-dose crossover study of 28 liver transplant recipients.[9] Systemic ganciclovir exposure
delivered by valganciclovir 900mg (41.7 g h/mL)
was comparable to that with intravenous ganciclovir
5 mg/kg (48.2 g h/mL) and higher than that with
oral ganciclovir 1000mg three times daily (20.7
2005 Adis Data Information BV. All rights reserved.

g h/mL).[9] These data suggest that exposure delivered by a valganciclovir 450mg dose would equal
that achieved with oral ganciclovir 3000mg. However, there are discrepancies between the figures for
oral ganciclovir in this study and that of Pescovitz et
al.[9] (28.0 g h/mL vs 20.7 g h/mL, respectively), which stem from the difference between the
estimation of 24 hour AUCs after single-dose and
steady-state dosing regimens. With oral ganciclovir
being administered three times daily, compared with
once daily for valganciclovir and intravenous ganciclovir, accumulation is significantly greater (approximately 25% as opposed to 5%). Thus, extrapolation of the data of Pescovitz et al.[9] to steady-state
would have given AUCs of approximately 26.0
g h/mL and 44.0 g h/mL from oral ganciclovir
(1000mg three times daily) and valganciclovir
(900mg once daily), respectively, which are figures
that strongly agree with the results of this study.
These findings highlight the appropriateness of valClin Pharmacokinet 2005; 44 (5)

506

ganciclovir 900mg once daily, adjusted for renal

function, for prophylaxis in SOT patients; a dose of
valganciclovir 450mg once daily would deliver systemic exposure distinctly lower than that of oral
ganciclovir 1000mg three times daily.
We observed relative systemic exposure of ganciclovir from valganciclovir to be approximately 8fold higher than that achieved with oral ganciclovir.
This large difference probably results from enhanced absorption of valganciclovir via a peptidemediated active transport system (PEPT1 and
PEPT2), which is similar to that previously described for valaciclovir.[11,24,25] The exposure of
ganciclovir delivered by valganciclovir allows exposures similar to those achieved with intravenous
ganciclovir as described earlier.
As with oral and intravenous ganciclovir, a minimum of approximately 8085% of ganciclovir delivered by valganciclovir is excreted in urine.[14]
Consequently, the pharmacokinetics of ganciclovir
is markedly altered in patients with renal impairment.[11,26,27] Dosage adjustment is required to ensure adequate drug exposure while avoiding the
adverse events (e.g. neutropenia) that are associated
with ganciclovir therapy.[5,15,22] The dosage of ganciclovir can be adjusted based on predicted CLCR, in
many cases using the Cockroft-Gault equation.[28]
An appropriate dosing algorithm facilitates the initial administration of valganciclovir in SOT recipients in clinical practice, as has been demonstrated
for ganciclovir in SOT recipients.[29] Suboptimal
ganciclovir exposures have been described in patients administered dosage according to an earlier
dosing algorithm based on CLCR.[8] In our study, the
dosing algorithm (originally developed for valganciclovir in patients who were renally impaired,
but otherwise healthy[11]) was successful in delivering consistent systemic exposure to ganciclovir in
patients whose renal function varied by almost an
order of magnitude. Analogous dose-AUC relationships would be expected for recipients of other
SOTs (e.g. lung), which suggests that valganciclovir
is appropriate for CMV prophylaxis in other types of
SOT.
2005 Adis Data Information BV. All rights reserved.

Wiltshire et al.

Conclusion
In conclusion, the population pharmacokinetic
model developed for ganciclovir after administration of valganciclovir and oral ganciclovir to SOT
recipients was validated and generated data were
consistent with those from other SOT studies. Valganciclovir produces systemic exposure to ganciclovir exceeding that attained with oral ganciclovir.
Average exposure to ganciclovir from valganciclovir was similar across liver, heart and kidney
transplant recipients. The dosing algorithm employed was successful in delivering comparable exposure to ganciclovir irrespective of large differences in renal function. The results of this study
indicate that valganciclovir is appropriate in circumstances requiring ganciclovir, but additionally provides convenient, once-daily oral administration in
patients at risk of CMV infection and disease.
Acknowledgements
This study was funded by Hoffman-La Roche Ltd, Basel,
Switzerland. Hugh Wiltshire is an employee of the sponsor.
Mark Pescovitz has received honoraria for speaking and is a
consultant to the sponsor. Atul Humar is a consultant for the
sponsor. Barbara Alexander, Emily Blumberg and Richard
Freeman have received honoraria for speaking for the sponsor.

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Correspondence and offprints: Dr Hugh Wiltshire, Roche

Products Ltd, 40 Broadwater Road, Welwyn Garden City,
HERTS AL7 3AY, UK.
E-mail: rene.bouw@roche.com

Clin Pharmacokinet 2005; 44 (5)