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TRANSPLANTATION

Oral valganciclovir leads to higher exposure to ganciclovir than intravenous

ganciclovir in patients following allogeneic stem cell transplantation
Hermann Einsele, Pierre Reusser, Martin Bornhäuser, Peter Kalhs, Gerhard Ehninger, Holger Hebart, Yves Chalandon,
Nicolaus Kröger, Bernd Hertenstein, and Frank Rohde, for the EBMT Working Group on Infectious Disease

Cytomegalovirus (CMV) infection is a ma- assessment of safety and efficacy. Pa- V-GCV was approximately 75% in individu-
jor complication after allogeneic stem cell tients without I-GVHD had a higher expo- als with or without I-GVHD grades I-II. No
transplantation (SCT). Valganciclovir (V- sure to GCV after V-GCV when compared severe GCV-related toxicity was observed
GCV) is an oral prodrug hydrolyzed to the with IV-GCV (area under the concentra- and efficacy and safety was comparable
anti-CMV drug ganciclovir (GCV). A ran- tion-time curve from drug administration (84-day follow-up). This supports the use
domized, multicenter, crossover, open- to last observed concentration after 12 of V-GCV in SCT, even in patients with
label clinical trial compared exposure to hours [AUC0-12] 53.8 ⴞ 17.97 ␮g/mL 䡠 h I-GVHD grades I-II. Due to higher expo-
GCV after V-GCV and intravenous GCV [mean ⴞ SD] vs 39.5 ⴞ 13.91; P < .001; sure after V-GCV compared with IV-GCV,
(IV-GCV) as preemptive therapy for CMV ratio of V-GCV/IV-GCV was 1.4; 90% confi- patients should be monitored carefully
disease in SCT. The primary objective dence interval [CI], 1.2-1.5). This was also for safety reasons. (Blood. 2006;107:
was to compare exposure to GCV in pa- true in patients with I-GVHD grades I-II 3002-3008)
tients with CMV infection stratified for (AUC0-12 52.9 ⴞ 21.75 vs 33.1 ⴞ 12.97 ␮g/
intestinal graft-versus-host disease (I- mL 䡠 h; P ⴝ .018; ratio 1.6; 90% CI, 1.3-
GVHD). Secondary objectives were the 2.0). Absolute bioavailability of GCV after © 2006 by The American Society of Hematology

Introduction
Cytomegalovirus (CMV) infection is a major cause of morbidity patients but relies on the availability of sensitive and specific CMV
and mortality after allogeneic stem cell transplantation (SCT).1,2 monitoring procedures.6-11
Currently, preemptive therapy for CMV infection has to be Valganciclovir (V-GCV; valganciclovir hydrochloride) is a
performed intravenously (ie, using intravenous ganciclovir [IV- monovalyl ester prodrug that, when administered orally, is rapidly
GCV; ganciclovir sodium] and/or foscarnet [Foscavir, trisodium hydrolyzed to GCV.12,13 It is indicated for the treatment of CMV
phosphonoformate]) and is associated with hospitalization, high retinitis in patients with acquired immunodeficiency syndrome
costs, and increased morbidity due to catheter-related complica- (AIDS) and for the prevention of CMV disease in high-risk kidney,
tions. In addition, new transplantation modalities (eg, reduced- heart, and kidney-pancreas transplantation patients. A previous
intensity conditioning protocols and haploidentical SCT) are study in liver transplant recipients has demonstrated that a dose of
associated with increased risks for late-onset CMV reactivation and 1 ⫻ 900 mg V-GCV results in a GCV AUC0-24 (area under the
disease. This underlines the need for an oral anti-CMV drug with concentration-time curve from drug administration to last observed
sufficient bioavailability that can be used for outpatient care. concentration after 24 hours) similar to those obtained with 1 ⫻ 5
Prophylactic drug treatment is used to prevent CMV reactiva- mg IV-GCV/kg body weight (BW).14 The safety and efficacy of its
tion in every patient at risk,3-5 whereas preemptive therapy means prophylactic use in solid organ transplantation (SOT) was compa-
initiating antiviral treatment only in patients with documented rable to 3 g of oral GCV.15 In addition, orally administered 2 ⫻ 900
CMV infection in order to prevent the development of CMV mg V-GCV was as effective as 2 ⫻ 5 mg IV-GCV/kg BW for the
disease.6-9 GCV preemptive therapy minimizes drug exposure to induction and maintenance therapy of acute CMV retinitis in

From the University of Würzburg, Department of Internal Medicine II, Transplantation (EBMT) Working Group for Infectious Disease appears in
Würzburg, Germany; University of Tübingen, Department of Internal Medicine the “Appendix.”
II, Division of Hematology, Oncology, Immunology and Rheumatology,
This study (MX16451) was sponsored by Hoffmann-La Roche AG (Grenzach-
Tübingen, Germany; University of Basel, Division of Hematology, University
Wyhlen, Germany) on behalf of F. Hoffmann-La Roche Ltd (Basel, Switzerland)
Hospital Basel and Hospital of Jura, Department of Internal Medicine,
in cooperation with H.E., P.R., M.B., P.K., G.E., H.H., Y.C., N.K., and B.H.
Porrentruy, Switzerland; University of Dresden, Department of Internal
Medicine I, Division of Hematology and Oncology, Dresden, Germany; Medical One of the authors (F.R.) has declared a financial interest in Hoffmann-La
University of Vienna, Department of Internal Medicine I, Bone Marrow Roche, whose products were studied in the present work. One of the authors
Transplantation Unit, Vienna, Austria; University of Geneva, Department of (F.R.) is employed by Hoffmann-La Roche, whose products were studied in the
Internal Medicine, Division of Hematology, Geneva, Switzerland; University of present work.
Hamburg, Eppendorf University Hospital, Bone Marrow Transplantation H.E. and P.R. contributed equally to this study.
Center, Hamburg, Germany; Hannover Medical School, Department of Internal
Medicine, Division of Hematology and Oncology, Hannover, Germany; and Reprints: Hermann Einsele, University of Würzburg, Department of Internal
Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany. Medicine II, Klinikstr. 6-8, 97070 Würzburg, Germany, e-mail: einsele_h@klinik.
uni-wuerzburg.de.
Submitted September 21, 2005; accepted November 23, 2005. Prepublished The publication costs of this article were defrayed in part by page charge
online as Blood First Edition Paper, December 13, 2005; DOI 10.1182/blood- payment. Therefore, and solely to indicate this fact, this article is hereby
2005-09-3786. marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
A complete list of the members of the European Group for Blood and Marrow © 2006 by The American Society of Hematology

3002 BLOOD, 1 APRIL 2006 䡠 VOLUME 107, NUMBER 7

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BLOOD, 1 APRIL 2006 䡠 VOLUME 107, NUMBER 7 VALGANCICLOVIR FOR CMV INFECTION IN SCT 3003

HIV-infected patients.16 The exposure to GCV (AUC0-24) after

V-GCV treatment was less in the HIV population compared with
patients after liver transplantation.
After SCT, graft-versus-host disease (GVHD) grades II-IV
develops in approximately 30% to 50% of patients,17 and intestinal
manifestations (I-GVHD) can alter the absorption of drugs from
the gut.18 Allogeneic SCT-related myeloablative chemotherapy and
total body irradiation are additional risk factors for malabsorption
in the early phase after SCT. V-GCV has already been advocated in
the medical literature for CMV preemptive therapy after allogeneic
SCT,17 but because of safety reasons pharmacokinetics (pk) data
need to be generated for the exposure to GCV as well as initial
safety and efficacy data.19 We addressed this need using a
randomized clinical trial.

Patients, materials, and methods

Study design

This was a prospective, randomized, multicenter, crossover, open-label

clinical trial with V-GCV and IV-GCV. The primary objective was to
compare the GCV AUC0-12 after administration of IV-GCV and V-GCV.
Secondary objectives were to assess safety and efficacy aspects for the 2
treatment groups at crossover and after completing the treatment. Approval
was obtained from the ethics committee at the University of Tübingen
(272/2001). Informed consent was provided according to the Declaration
of Helsinki.
The study patients were adults who underwent an allogeneic SCT and
were at risk for CMV disease (Table 1). Patients were recruited and
stratified according to the presence of I-GVHD. The patients who received
transplants were screened for CMV infection using Cobas Amplicor CMV
MONITOR (CMV-M; Roche Diagnostics, Mannheim, Germany), a commer-
cially available quantitative polymerase chain reaction (PCR) test for
plasma specimens with a limit of detection of 400 copies of CMV
DNA/mL.11 Patients who tested positive up to day 100 after SCT were
Figure 1. Study design. After completion of pharmacokinetic sampling on day 11, all
eligible for randomization. Other eligibility criteria were ability to take oral
treatment decisions were made based on the results of the Cobas Amplicor CMV
medication, an absolute neutrophil count (ANC) greater than 0.75 ⫻ 109/L MONITOR (CMV-M) assay. Using this assay, responders were defined as patients
(750 cells/␮L) on 2 consecutive visits within 10 days prior to randomi- with CMV DNA less than 400 copies/mL. Nonresponders were defined as patients
zation, and a negative serum pregnancy test at randomization for with CMV DNA at least 400 copies/mL. V-GCV indicates valganciclovir; and IV-GCV,
female patients. intravenous ganciclovir.
Patients were ineligible if they had established CMV disease or had
received any systemic anti-CMV therapy within 30 days prior to randomiza-
nia (ANC ⬍ 0.75 ⫻ 109/L [750 cells/␮L]), or in the case of severe
tion. Patients unable to take oral medication and those with impaired renal
neutropenia (ANC ⬍ 0.50 ⫻ 109/L [500 cells/␮L] for 2 or more consecu-
function (creatinine clearance ⬍ 0.41 mL/s [25 mL/min]) were also
tive days). Any dose adjustments due to changing renal function during the
ineligible. Patients showing less than 30% or more than twice the average
initial 14 days of treatment led to the exclusion of the patient from the pk
weight for their sex, age, and height were excluded (determined by the
analysis.
Metropolitan Life Insurance Company Weight Tables, National Center for
Health Statistics, Hyattsville, MD).
Pharmacokinetics
Eligible patients were randomized to 1 of 2 treatment groups (Figure
1): group A received 900 mg oral V-GCV (2 ⫻ 900 mg/d) for 7 days, During the initial 14-day treatment period pk profiles of GCV were obtained
crossing over on day 8 to IV-GCV given twice daily (2 ⫻ 5 mg/kg after administration of V-GCV and IV-GCV in each of both study arms
BW/d) until day 14; group B was treated vice versa. Compliance with (crossover design). Pk assessments were scheduled at days 4 and 11 (Figure
the treatment regimen was assessed by maintaining drug dispensing 1). Plasma samples were drawn 30 minutes prior to the dosing interval
records, and treatments were administered by clinical staff. For the (minimal concentration [Cmin]); at administration of study drug (T0);
purposes of the study, the administration of 90% of the planned study 30 minutes thereafter; and subsequently 1, 2, 3, 4, 6, 8, and 12 hours after
medication throughout the treatment period (until day 14) was consid- dosing. GCV plasma levels were used to generate individual pk profiles and
ered adequate compliance. Patients experiencing impaired renal func- to calculate the exposure to GCV (AUC0-12) following V-GCV and IV-GCV
tion (creatinine clearance ⬍ 1.00 mL/s [60 mL/min]) received a reduced administration. Crossover to the second study medication was performed on
dose of IV-GCV or V-GCV according to the manufacturer’s recommen- day 8. A washout period was not applicable under clinical conditions for
dation. Individual decisions about the duration of therapy were made safety reasons (ongoing CMV infection), but pk analysis confirmed that
based on the results of CMV-M (Figure 1). All patients were monitored 10 GCV half-lives were sufficient to prevent any overlapping effect
for 84 days (safety follow-up). resulting from the former study drug. No fasting period was required but a
For safety reasons, the screening of vital signs, laboratory parameters standardized breakfast was provided for patients receiving V-GCV (study
for renal impairment, and analysis of the ANC were performed daily. drug was swallowed within 10 minutes of breakfast [T0]). For this study a
Hematopoietic growth factors could be given in case of moderate neutrope- standard breakfast was comparable to the following: bowl of cereal
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3004 EINSELE et al BLOOD, 1 APRIL 2006 䡠 VOLUME 107, NUMBER 7

(cornflakes) with 100 mL whole milk; 2 slices toast with butter, marmalade,
and cheese/sausage; 100 mL fresh orange juice; 150 mL decaffeinated tea or
Results
coffee. The dose of IV-GCV was given over a period of 1 hour at the rate of
50 mL/h using an intravenous infusion pump. For IV-GCV, T0 was the start Characteristics of the patients
of the infusion. Blood samples were collected using a catheter according to
a standardized procedure in order to prevent any contamination. Samples Between February 2002 and July 2003, 48 allograft recipients were
were analyzed by Analytico Research B.V. (Bergschot, Breda, The Nether- randomized to treatment: 26 to group A (receiving V-GCV first) and 22
lands) using high-pressure liquid chromatography analysis and the follow- to group B (receiving IV-GCV first). In each group there were 3 patients
ing parameters were calculated for GCV: area under the concentration-time with I-GVHD (Table 1) as defined clinically (n ⫽ 1) or by histopathol-
curve from drug administration to last observed concentration after 12 ogy (n ⫽ 5; Table 2). Twenty patients were excluded from the pk
hours (AUC0-12), maximal concentration (Cmax), minimal concentration analysis due to 23 protocol violations (n ⫽ 9 in group A and n ⫽ 11 in
(Cmin), time to Cmax (tmax), and half-life (t1/2). It was accepted that up to one group B; patients could have more than one protocol violation leading to
pk sample was not evaluable per pk profile. Absolute bioavailability of exclusion from the pk analysis); these were patients who received the
V-GCV was calculated as follows: [AUC0-12(GCV after V-GCV)/ incorrect dose of IV-GCV and/or V-GCV (eg, due to dose adjustment for
dose(GCV after V-GCV)]/[AUC0-12(IV-GCV)/dose(IV-GCV)], where GCV after V- changes in creatinine clearance or the administered dose was too high or
GCV values are expressed in GCV equivalents, calculated as follows: too low by error; this occurred in 8 patients), discontinued the study drug
doseV-GCV ⫻ molecular weight of GCV (free base)/molecular weight of
without completing both pk profiles (this occurred in 8 patients), had
V-GCV (free base) ⫽ doseV-GCV ⫻ 255/354.4.
violations in sampling (this occurred in 6 patients), or were entered more
than 200 days after SCT (this occurred for 1 patient). No patients were
CMV monitoring excluded from the pk analysis specifically for a lack of compliance with
study medication (⬍ 90% of the planned study medication until day 14),
Plasma CMV monitoring was performed routinely after SCT and continued
and no patients with I-GVHD were excluded from the pk analysis due to
during treatment and safety follow-up using CMV-M.7,10,11 Eligibility for
protocol violations. Three patients who were randomized after testing
randomization and all decisions regarding antiviral treatment were based on
the results obtained with CMV-M (Figure 1).
positive with an in-house PCR assay but without being tested positive by
CMV-M during the screening period were excluded from the efficacy
analysis. Therefore pk parameters were determined for 28 patients
Outcome parameters (17/26 group A and 11/22 group B; n ⫽ 22 for patients without I-GVHD
The primary end point was the GCV AUC0-12 after V-GCV compared with
and n ⫽ 6 for patients with I-GVHD); 45 patients (24/26 group A and
IV-GCV based on the V-GCV/IV-GCV ratio. Efficacy was monitored 21/22 group B) were included in the efficacy analysis and all 48
regarding time to first response by treatment group determined as plasma randomized patients in the safety analysis. One I-GVHD patient had
CMV DNA clearance proven by CMV-M–negative testing (CMV DNA severe I-GVHD grade III (Table 2) and, because of proven severe
⬍ 400 copies/mL) and the incidence of CMV disease until day 84 malabsorption, this patient is presented separately (n ⫽ 5 for patients
according to previously reported criteria.20 Safety analysis was based with I-GVHD grades I-II).
primarily on the incidence of serious adverse events (SAEs), CMV-related Dose adjustments due to changes in creatinine clearance
mortality, 100-day mortality, and overall mortality by treatment group.The occurred 7 times in 4 patients. During the study 9 of 48 patients
numbers of patients with ANC values less than 1.0 ⫻ 109/L (1000 cells/␮L) discontinued treatment with V-GCV and 6 of 48 treatment with
and less than 0.5 ⫻ 109/L (500 cells/␮L) at days 8, 15, and 22 were also
compared between treatment groups. Table 1. Baseline characteristics of the patients
Group A, Group B,
val/gan; gan/val;
Statistical analysis n ⴝ 26 n ⴝ 22

Patients were randomized using a dynamic treatment allocation procedure Age, y* 44.7 ⫾ 12.91 44.9 ⫾ 12.60
and stratified by the presence of I-GVHD.21 The results were summarized Male sex, no. (%) 15 (57.7) 15 (68.2)
and presented using summary statistics. A Kaplan-Meier analysis22 was Ethnic origin, no. (%)
used to estimate time to first response between groups A and B. All pk White 26 (100) 21 (95.5)
parameters were analyzed separately in patients with and without I-GVHD. Other 0 (0.0) 1 (4.5)
Geometric means were calculated for concentration-related parameters. For Body mass index, kg/m2* 23.3 ⫾ 3.96 23.2 ⫾ 3.39
this exploratory study, no sample size calculation was performed but it was Intestinal GVHD, no. (%) 3 (11.5) 3 (13.6)
planned to have a minimum of 20 patients without I-GVHD with an Day of randomization after transplantation, d 51.5 ⫾ 36.98 41.7 ⫾ 13.91
CMV status donor/recipient, no. (%)
evaluable pk profile.
Positive/positive 17 (65.4) 12 (54.5)
For the primary end point AUC0-12 of GCV after V-GCV compared with
Positive/negative 1 (3.8) 3 (13.6)
IV-GCV, the ratio of AUC0-12 means (V-GCV/IV-GCV) and the 2-sided
Negative/positive 8 (30.8) 7 (31.8)
90% confidence interval for the ratio of AUC0-12 means were calculated.
Donor/recipient relationship, no. (%)†
AUC0-12 was calculated using the linear trapezoidal rule. An analysis of
HLA-identical sibling donor 14 (53.8) 8 (36.4)
variance with the factors patient, sequence, period, and treatment was
Matched unrelated donor 9 (34.6) 9 (40.9)
applied to the logarithmically transformed variable in AUC0-12 using the Mismatched related donor 0 (0.0) 2 (9.1)
main effects model to estimate the difference between treatment sequences Mismatched unrelated donor 3 (11.5) 2 (9.1)
and within patient variance (␴2) and using the 2-sided 90% confidence Nonmyeloablative low intensity SCT, no. (%) 6 (23.1) 6 (27.3)
interval for the difference. To obtain the estimates of the ratio of AUC0-12 CMV-M positive, no.(%) 24 (92.3) 21 (95.5)
means and the 2-sided 90% confidence interval for the ratio of AUC0-12
means, the derived least squares means difference and the respective Positive CMV infection was determined as CMV DNA ⱖ 400 copies/mL. All
plus/minus values are mean ⫾ SD.
confidence limits were back transformed using the exponential function. In val indicates valganciclovir; gan, ganciclovir.
addition, pk parameters were compared using a paired t test. Safety and *Based on n ⫽ 24 (group A) and n ⫽ 21 (group B).
efficacy parameters were analyzed descriptively for the 2 groups. †Based on n ⫽ 26 (group A) and n ⫽ 21 (group B).
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BLOOD, 1 APRIL 2006 䡠 VOLUME 107, NUMBER 7 VALGANCICLOVIR FOR CMV INFECTION IN SCT 3005

Table 2. Clinical characteristics of intestinal GVHD (I-GVHD) patients

GVHD grading
Biopsy-proven GCV pk after V-GCV
Patient Overall I-GVHD I-GVHD administration Remark

Group A, val/gan
1 I I Yes Adequate Diarrhea ⬎ 500 mL/day
2 III II Yes Adequate Diarrhea ⬎ 1000 mL/day
3 II III Yes Severe malabsorption Severe I-GVHD (diarrhea ⬎ 1000 mL/day) for
weeks, decreasing prior to randomization;
GVHD of the liver (grade II)
Group B, gan/val
1 II I No* Adequate Diarrhea (ⱕ 10 ⫻ in total 600 mL/day); severe
GVHD of the skin (grade III)
2 II II Yes Adequate Outpatient care
3 III II Yes Adequate Outpatient care

val indicates valganciclovir; and gan, ganciclovir.

*This patient had diarrhea between 500 and 1000 mL/day and a coexisting cutaneous aGVHD grade III, indicating the diarrhea to be due to intestinal GVHD.

IV-GCV. Discontinuation from treatment before both pk profiles 1.4). A significant difference was also observed in exposure to
were complete also led to exclusion from the pk analysis (see GCV for 5 patients with I-GVHD grades I-II between treatment
above). The main reason for discontinuation was treatment failure with V-GCV (AUC0-12 52.9 ⫾ 21.75 ␮g/mL 䡠 h) and IV-GCV
(2 and 3 patients for V-GCV and IV-GCV, respectively), with all (AUC0-12 33.1 ⫾ 12.97 ␮g/mL 䡠 h; P ⫽ .018, paired t test for
these patients showing an increase in CMV DNA during treatment. difference; Table 3). The V-GCV/IV-GCV ratio within this subpopu-
Only 4 patients discontinued due to dose adjustments (2 patients lation was 1.6. Profiles for blood levels of GCV are shown in
each for V-GCV and IV-GCV). Other reasons for discontinuation Figure 2 for both populations. For one patient with biopsy-proven
were adverse events (2 patients from V-GCV for a central line severe I-GVHD grade III, oral absorption following V-GCV was
infection and neutropenia, respectively, and 1 patient from IV-GCV inadequate, and a low trough level (Cmin; 0.4 ␮g/mL) and an
due to neutropenia) and protocol violations (3 patients for V-GCV). inadequate AUC0-12 (14.8 ␮g/mL 䡠 h) following dosing were
documented.
Pharmacokinetics
The absolute bioavailability of GCV after V-GCV in patients
In patients without I-GVHD (n ⫽ 22), using a fixed oral dose of without I-GVHD was 76.4% ⫾ 18.27% (mean ⫾ SD; n ⫽ 22) and
V-GCV 2 ⫻ 900 mg/d led to a significantly higher exposure to 74.5% ⫾ 14.39% in SCT patients suffering from I-GVHD grades
GCV (AUC0-12 53.8 ⫾ 17.97 ␮g/mL 䡠 h [mean ⫾ SD]) compared I-II (n ⫽ 5).
with a BW-adjusted dose of IV-GCV 2 ⫻ 5 mg/kg/d (AUC0-12 Efficacy
39.5 ⫾ 13.91 ␮g/mL 䡠 h; P ⬍ .001, paired t test for difference).
The V-GCV/IV-GCV ratio was 1.4 (Table 3). For 3 patients without All 45 patients analyzed for efficacy recorded a positive CMV-M
I-GVHD, creatinine clearance was slightly below 1.00 mL/s test at randomization. The Kaplan-Meier estimates of time to first
(60 mL/min) at the day of pk analysis (0.98, 0.95, 0.93 mL/s [59, response and cumulative responders within the initial 14-day
57, 56 mL/min]). Excluding these patients from the pk analysis treatment period are provided in Figure 3.
(n ⫽ 19) does not alter the overall result (AUC0-12 52.1 ⫾ 15.26 Overall, at the end of the safety follow-up (day 84), the total
␮g/mL 䡠 h vs AUC0-12 38.5 ⫾ 13.99 ␮g/mL 䡠 h for V-GCV vs number of patients with response to therapy (CMV DNA ⬍ 400
IV-GCV, respectively; P ⬍ .001, paired t test for difference; ratio copies/mL) was 37 of 45 (82.2%): 21 of 24 in group A and 16 of 21

Table 3. Pharmacokinetic parameters for ganciclovir after treatment with intravenous ganciclovir and oral valganciclovir
No. of Body weight, AUC0-12, Cmax, Cmin,
patients kg ␮g/mL 䡠 h ␮g/mL ␮g/mL Tmax, h t1/2, h

Patients without intestinal GVHD

Oral valganciclovir 22 72.26 ⫾ 11.49 53.8 ⫾ 17.97 8.8 ⫾ 2.38 1.7 ⫾ 0.94 2.7 ⫾ 0.75 4.2 ⫾ 1.08
Intravenous ganciclovir 22 72.26 ⫾ 11.49 39.5 ⫾ 13.91 10.3 ⫾ 2.12 1.0 ⫾ 0.65 1.1 ⫾ 0.64 3.4 ⫾ 0.81
Ratio, 90% CI (range) 22 72.26 ⫾ 11.49 1.4 (1.2-1.5) 0.8 (0.8-0.9) ND ND ND
P 22 72.26 ⫾ 11.49 ⬍ .001 .013 ⬍ .001 ⬍ .001 ⬍ .001
Patients with intestinal GVHD I-II
Oral valganciclovir 5 60.22 ⫾ 5.06 52.9 ⫾ 21.75 8.0 ⫾ 3.25 1.9 ⫾ 0.77 2.9 ⫾ 0.82 6.1 ⫾ 1.92
Intravenous ganciclovir 5 60.22 ⫾ 5.06 33.1 ⫾ 12.97 10.6 ⫾ 3.30 0.7 ⫾ 0.36 1.0 ⫾ 0.07 3.4 ⫾ 0.74
Ratio, 90% CI (range) 5 60.22 ⫾ 5.06 1.6 (1.3-2.0) 0.7 (0.5-1.0) ND ND ND
P 5 60.22 ⫾ 5.06 .018 .084 .016 .007 .041
Patient with intestinal GVHD III and severe malabsorption
Oral valganciclovir 1 49.7 14.8 2.6 0.4 2.0 3.4
Intravenous ganciclovir 1 49.7 46.6 13.2 1.1 2.0 3.0

P values are for paired t tests for difference. All plus/minus values are mean ⫾ SD.
AUC indicates the area under the concentration-time curve; Cmax, the maximal concentration; Cmin, the minimum concentration; Tmax, the time to Cmax; t1/2, the half-life of
ganciclovir; and ND, not done.
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3006 EINSELE et al BLOOD, 1 APRIL 2006 䡠 VOLUME 107, NUMBER 7

Table 4. Serious adverse events and overall mortality

Group A, Group B,
val/gan; gan/val;
n ⴝ 26 n ⴝ 22

Serious adverse events*

Total no.of patients with a serious adverse
event (%) 15 (57.7) 16 (72.7)
Myelotoxicity (%) 3 (11.5) 3 (13.6)
Anemia 2 0
Febrile neutropenia 0 1
Severe neutropenia†/pancytopenia 1 1
Thrombocytopenic purpura 0 1
Gastrointestinal disorders (%) 2 (7.7) 1 (4.5)
Diarrhea 0 1
Gastrointestinal hemorrhage 2 0
Secondary infections (%) 8 (30.8) 8 (36.4)
Fungal infection 1 0
Recurrent CMV infections 3 4
CMV interstitial pneumonia (CMV-IP) 0 2§
Total no. of patients w/serious adverse event
leading to withdrawal (%) 0 (0.0) 1 (4.5)
Severe neutropenia 0 (0.0) 1 (4.5)
Mortality
Overall mortality (%)‡ 2 (7.7) 4 (18.2)
100-day mortality 1㛳 3¶
Figure 2. Blood levels for ganciclovir over 12-hour dosing period (mean ⴞ SD). Fungal pneumonia 1; day 32 0
Plasma samples were drawn 30 minutes prior to the dosing interval; at administration Non-CMV respiratory failure 0 1; day 23
of study drug (T0); 30 minutes thereafter; and subsequently 1, 2, 3, 4, 6, 8, and 12 Progressive disease 0 2; days 62 and 76
hours after dosing. GCV plasma levels (mean ⫾ SD) were determined using
high-pressure liquid chromatography and were used to generate pk profiles following val indicate valganciclovir; gan, ganciclovir.
administration of valganciclovir (V-GCV) and intravenous ganciclovir (IV-GCV). (A) *Details are provided for selected serious adverse events.
Pk profiles for patients without intestinal graft-versus-host disease (I-GVHD; n ⫽ 22). †ANC ⬍ 500 cells/␮L for 2 or more consecutive days.
(B) Pk profiles for patients with I-GVHD grades I-II (n ⫽ 5). One patient with I-GVHD ‡No deaths occurred in patients with intestinal GVHD.
grade III is not included. Time points are offset for clarity. §Both patients who developed CMV-IP had completed study drug administration
since 11 days (n ⫽ 1) and 40 days (n ⫽ 1), respectively, and recovered completely.
㛳One additional patient died after safety follow-up from relapse of acute myeloid
leukemia.
in group B (87.5% vs 76.2%). For 9 of 45 (20.0%) patients, CMV
¶One additional patient died from RSV pneumonia at day 110 after randomiza-
infection recurred after first response to treatment (7/21 [33.3%] in tion.
group A and 2/16 [12.5%] in group B).
Only 2 patients developed CMV disease, both cases occurred
during the follow-up period on days 40 and 55 in group B. Both medication–related mortality and the overall safety was excellent
patients developed CMV interstitial pneumonia (CMV-IP) and with regard to SCT patients. The overall incidence, severity, and
responded to IV-GCV plus CMV hyperimmunoglobulin. type of adverse events (AEs) were similar between treatments
(25/26 [96.2%] experienced 264 AEs and 22/22 [100%] experi-
Safety enced 229 AEs in group A and group B, respectively).
The primary safety analysis did not show major differences Pyrexia was the most common AE reported for 12 (46.2%) of 26
patients in group A and 11 (50.0%) of 22 patients in group B.
between group A and group B (Table 4). There was no study
Neutropenia was reported as an AE for 5 (19.2%) of 26 patients in
group A and 8 (36.4%) of 22 patients in group B. For patients with
ANC counts at days 8, 15, and 22, the numbers of patients with
ANC values less than 1.0 ⫻ 109/L (1000 cells/␮L) in group A and
group B were 3 (14.3%) of 21 and 4 (20.0%) of 20 at day 8, 2
(10.5%) of 19 and 3 (17.6%) of 17 at day 15, and 5 (31.3%) of 16
and 2 (15.4%) of 13 at day 22, respectively. Patients with ANC
values less than 0.5 ⫻ 109/L (500 cells/␮L) in group A and group B
were 0 and 1 (5.0%) of 20 at day 8, none at day 15, and 2 (12.5%) of
16 and 1 (7.7%) of 13 at day 22, respectively. Hematopoietic
growth factors were administered to a total of 17 patients during the
study (11/26 [42.3%] in group A and 6/22 [27.3%] in group B).

Figure 3. Kaplan-Meier curves showing time to first response within the first 14 Discussion
days of treatment. Responders were identified using the Cobas Amplicor CMV
MONITOR (CMV-M) assay. The cumulative proportion of patients with a first
response to treatment (CMV DNA ⬍ 400 copies/mL) and the cumulative number of This is the first clinical trial investigating an oral V-GCV induction
responders are provided. dose for preemptive therapy in patients with CMV infection
 From www.bloodjournal.org by guest on October 8, 2019. For personal use only.

BLOOD, 1 APRIL 2006 䡠 VOLUME 107, NUMBER 7 VALGANCICLOVIR FOR CMV INFECTION IN SCT 3007

following allogeneic SCT. A twice-daily dose of 900 mg V-GCV adaptation of GCV is required. Alteration of renal function within
led to a significantly higher exposure to GCV (AUC0-12) than the study period was a major reason that randomized patients were
2 ⫻ 5 mg/kg/d IV-GCV, even in patients with I-GVHD grades I-II. not eligible for pk analysis. However it must be noted that the
The absolute bioavailability of GCV in SCT patients was compa- exclusion of 3 patients without I-GVHD with a known reduced
rable for patients with I-GVHD grades I-II and without I-GVHD creatinine clearance from the pk analysis did not alter the overall
(approximately 75%). This excellent bioavailability in the SCT result and the exposure to GCV after V-GCV treatment was still
population was linked with an increased GCV AUC0-12 during higher compared with IV-GCV treatment.
V-GCV induction therapy when compared with HIV patients Clearance of viral load in patients who received V-GCV as
treated for acute CMV retinitis (53.8 ⫾ 17.97 vs 32.8 ⫾ their initial therapy was similar to patients who received
10.1 ␮g/mL 䡠 h).16 A potential damage to the intestinal tract IV-GCV first (response rates). Only 2 patients developed CMV
following myeloablative conditioning therapy may contribute to disease (CMV-IP) during follow-up when receiving no antiviral
the increase in bioavailability of GCV after V-GCV in SC chemotherapy and recovered completely. No patient died due to
transplant recipients when compared with HIV and SOT patients. CMV disease or from events related to study drug. The rate of
For both HIV and SOT patients the bioavailability of GCV after serious neutropenia was low and favorable when compared with
V-GCV treatment was demonstrated to be approximately 60%, earlier reports on prophylactic or preemptive treatment with
although overall exposure was different between HIV and SOT GCV after SCT.3-6,23,24
patients (AUC0-24 34.9 vs 41.7 ␮g/mL 䡠 h).14,16 As reasons to In conclusion, the exposure to GCV after the administration
explain the differences in exposure variations in glomerular of 1800 mg/d V-GCV for preemptive therapy is significantly
filtration and tubular secretion of GCV, underlying disease and higher compared with standard therapy using 10 mg/kg/d
comedication between these patient populations are possible. IV-GCV. This is also true for patients suffering from I-GVHD
The concentration time profile (AUC0-12) of GCV following grades I-II. Taking into account more than one decade of
V-GCV treatment demonstrated a slower rate of absorption, with a experience in using IV-GCV in SCT, the authors do not consider
lower maximal blood concentration (Cmax) but a longer time to that a change in the standard dosing of this medication should be
elimination (t1/2), leading to higher dosing interval trough levels considered (10 mg/kg/d IV-GCV). Moreover there should be
(Cmin) compared with IV-GCV treatment. This was observed both careful consideration before transferring these patients to oral
for patients with and without I-GVHD grades I-II, indicating that preemptive therapy using V-GCV, as there will be a significantly
these patients can be offered treatment with oral V-GCV. Due to the higher exposure to GCV and currently V-GCV is not approved
observed malabsorption of GCV after V-GCV treatment in one for use in SCT (any use would be “off-label”). Daily ANC and
patient suffering from severe I-GVHD grade III, the authors creatinine clearance monitoring would be essential tools to
recommend IV-GCV treatment for patients with severe I-GVHD improve the safety of V-GCV in SCT patients, and in the case of
associated with significant malabsorption. reduced renal function it is essential to adjust the dose of V-GCV
The lower GCV Cmax observed with oral V-GCV treatment than appropriately. Therapeutic drug monitoring of GCV concentra-
IV-GCV treatment is a known phenomenon for pk comparisons of tions is also possible and may be an option if dose finding for
V-GCV and IV-GCV16 and was statistically significant in the V-GCV is a problem in a single patient. Overall, the results
current trial. However, previous authors have indicated that the support the use of short-term preemptive therapy with V-GCV in
clinical efficacy of GCV is driven by total drug exposure (AUC) combination with adequate CMV monitoring,25,26 but the cross-
and not by Cmax,13 indicating that a lower Cmax should not compromise over design means that clear statements regarding efficacy and
any potential efficacy. In the current paper, the AUC0-12 of GCV was safety cannot be made and there is still a need for a larger,
significantly greater after V-GCV treatment when compared with a confirmative study evaluating the safety and efficacy of V-GCV
standard, effective dose of IV-GCV and is higher when compared with preemptive therapy in patients after allogeneic SCT.
HIV patients treated for acute CMV retinitis.
Because this pk trial was performed under clinical conditions, a
washout period was not feasible for safety reasons. However, for Acknowledgments
the pk analysis, no contamination issues were expected after
crossover, as the steady-state of GCV has been described to be The authors would like to thank all members of the study group for
completed within 24 hours and in our protocol the patient was their participation in this study.
treated for at least 72 hours before the pk profile was generated. The
crossover design also allowed determination of intersubject/patient
variability in the GCV pk profile following administration of
Appendix
IV-GCV and V-GCV, respectively. In addition, the bioavailability
of GCV can be estimated in this patient population. A disadvantage The study group was as follows: Einsele H (University of Würzburg,
of this crossover design was that safety and efficacy aspects were Würzburg, Germany); Hebart H, Schmalzing M (University of Tübingen,
not attachable to the individual study drug intervals. Patients Tübingen, Germany); Reusser P, Gratwohl A (Division of Hematology,
received both treatments in a short time frame and there is a known University Hospital Basel, and Hospital of Jura, Porrentruy, Switzerland);
delay in the onset of key safety issues (ie, neutropenia) and readout Bornhäuser M, Ehninger G (University of Dresden, Dresden, Germany);
parameters for efficacy (ie, CMV viral load clearance). To confirm Kröger N, Kratochwille A, Zander AR (University of Hamburg, Hamburg,
Germany); Hertenstein B, Mischak-Weissinger EM, Buchholz S, Ganser A
the safety and efficacy of V-GCV treatment in SCT, another
(Hannover Medical School, Hannover, Germany); Kalhs P, Rabitsch W
prospective clinical trial is necessary. (Medical University of Vienna, Vienna, Austria); Chalandon Y, Chapuis B
Renal toxicity was minimal, and dose adjustments due to (University of Geneva, Geneva, Switzerland); Schüler P, Raab C, Dawes K,
decreased creatinine clearance were performed in only 4 of 48 Bruns R, Reister M, Leskopf W, Esken W, Straub C, Bruckmann K, Strunck
patients. However physicians should be aware that renal function E, Wiecker B (PRA International, Mannheim, Germany); Rohde F, Birras
can change rapidly in SCT patients and that immediate dose C, Rose MT (Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany).
 From www.bloodjournal.org by guest on October 8, 2019. For personal use only.

3008 EINSELE et al BLOOD, 1 APRIL 2006 䡠 VOLUME 107, NUMBER 7

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2006 107: 3002-3008

doi:10.1182/blood-2005-09-3786 originally published online
December 13, 2005

Oral valganciclovir leads to higher exposure to ganciclovir than

intravenous ganciclovir in patients following allogeneic stem cell
transplantation
Hermann Einsele, Pierre Reusser, Martin Bornhäuser, Peter Kalhs, Gerhard Ehninger, Holger Hebart,
Yves Chalandon, Nicolaus Kröger, Bernd Hertenstein and Frank Rohde

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