Clinical Trial Result Information

Protocol number
ML16420

Title of Study
The pharmacokinetics of ganciclovir following a dose of valganciclovir vs iv ganciclovir in bone marrow transplant or human stem cell transplant (BMT/HSCT) patients with stable graft-versus-host disease (GVHD) who have gut involvement

Sponsor
Roche Laboratories Inc.

Company division
Pharmaceutical

Product name
Valcyte

Generic name
valganciclovir

Therapeutic area
Cytomegalovirus infections

Clinical study summary
This was a single-dose, open-label, randomized crossover study of the pharmacokinetics and safety of valganciclovir (Valcyte) in patients with bone marrow transplant/human stem cell transplant (BMT/HSCT) with stable graft-versus-host disease (GVHD) and gut involvement. Patients were randomly assigned to a sequence of 2 treatments: a single oral dose of Valcyte 900 mg or a single intravenous (iv) administration of ganciclovir 5 mg/kg. There was a minimum washout period of 2 days between treatments.

Study center(s)
4 centers in the United States.

Phase of development
II

Objectives
Primary: To determine area under the plasma concentration–time curve (CV-AUC_0-∞ ) of ganciclovir after a single oral dose of 900 mg Valcyte compared with the CV-AUC_0-∞after a single iv dose of 5 mg/kg ganciclovir in patients who have undergone BMT/HSCT and have stable GVHD with gut involvement.

Secondary: (1) To describe the pharmacokinetic parameters of ganciclovir and Valcyte after a single dose of ganciclovir or Valcyte in this same population; and (2) To assess the safety of the 2 drugs in these patients.

Methodology
After fasting from midnight, patients ate a standard breakfast and then received the designated treatment within 10 minutes. Patients received either oral Valcyte 900 mg or an iv infusion of ganciclovir 5 mg/kg over 1 hour. Blood samples were drawn for pharmacokinetic analysis at multiple time intervals. Plasma concentrations of ganciclovir were determined by a specific and validated liquid chromatography–mass spectrometry analytical method. Measurements of vital signs, hematology, and blood chemistry, along with urinalysis, were performed at screening and as prescribed by the protocol.

Number of patients (planned/analyzed)
24

Diagnosis and main criteria for inclusion
BMT/HSCT patients with stable GVHD and gut involvement

Test product, dose and mode of administration or test procedure
Valcyte 900 mg given as a single oral dose of two (2) 450-mg tablets after a meal; 24 hours over 2 days in study center for each dosing period.

Duration of treatment
Sequence of 2 treatments (2 days per treatment), with a minimum 2-day washout period between treatments

Reference therapy, dose and mode of administration or reference procedure
Single iv administration of ganciclovir 5 mg/kg over 1 hour.

Criteria for evaluation (efficacy, safety)
AUC CV-AUC_0-∞of ganciclovir after a single oral dose of 900mg Valcyte or a single i.v. dose of ganciclovir; pharmacokinetic parameters of ganciclovir after the two treatments.; safety parameters.

Statistical methods
Demographics and baseline characteristics were summarized by descriptive statistics. An analysis of variance model for the 2-way crossover design was used to assess the ratio of the means of the CV-AUC_0-∞ values for ganciclovir after oral Valcyte 900 mg vs iv ganciclovir 5 mg/kg. Additional pharmacokinetic parameters were summarized by treatment using descriptive statistics. Safety parameters were summarized by treatment using descriptive statistics.

Summary (efficacy, safety, other results)
PK – AUC0-∞ values ranged widely, but mean values for valganciclovir and ganciclovir were similar, 52.1 and 53.8 μg.h/mL respectively. Mean coefficient of variation (CV)-AUC values also were similar for the 2 drugs: the CV-AUC_0-t was 37.1% for valganciclovir and 37.2% for ganciclovir; and the CV-CV-AUC_0-∞ was 40.5% for valganciclovir and 39.9% for ganciclovir. The mean C_max of ganciclovir was twice as high as that of valganciclovir tablets, while the mean T_max was more than 3 times shorter with ganciclovir than valganciclovir. Mean elimination rate constant values for both drugs were equivalent, and the elimination half-life mean values were almost identical.

Safety – Overall, 8 patients reported a total of 19 adverse events: 6 patients reported 8 adverse events during the Valcyte treatment period, and 5 patients reported 11 events during the ganciclovir treatment period. All events were either mild or moderate in intensity. Two events in 1 patient (dizziness and defect in visual field) were considered related to ganciclovir; both events resolved without sequelae. There were no serious adverse events, nor did any patient die during the study.

The gastrointestinal (GI) system was cited more frequently than other body systems, with 2 patients reporting 5 adverse events: 1 patient reported nausea, vomiting, and diarrhea after iv ganciclovir; the patient also experienced nausea during Valcyte administration. A second patient had GI bleeding during Valcyte treatment.

Three patients reported respiratory system events: 1 patient had nasal congestion during treatment with ganciclovir; 1 reported coughing during treatment with ganciclovir; and 1 reported coughing during treatment with Valcyte. Two patients reported dizziness during ganciclovir administration; 1 of these patients also reported a defect in the visual field during this treatment period, while the other reported blurred vision. No nervous system or eye disorders were reported during the Valcyte treatment period.

Conclusions
Non-inferiority of Valcyte compared with ganciclovir was concluded based on the primary pharmacokinetic parameter CV-AUC_0-∞ as well as the secondary parameter CV-AUC_0-t. The lower limits of the 1-sided 95% confidence interval of the ratio of least square means for both AUCs for ganciclovir following Valcyte vs iv ganciclovir were higher than 80%. Adverse events were similar to those seen in other studies with Valcyte, with no deaths or serious adverse events reported. Based on the safety and pharmacokinetic profiles seen in the present study, oral Valcyte may be a viable alternative to ganciclovir in this type of patient population.

Publications (references, if available)
Winston D. Pharmacokinetics of ganciclovir following oral valganciclovir versus intravenous ganciclovir in allogeneic hematopoietic stem-cell transplant patients with stable graft-versus-host disease of the gastrointestinal tract. Poster presented at the American Society of Hematology 46th Annual Meeting. December 4-7,2004, San Diego, California

Date of report
3/4/2005