Cytomegalovirus Infections
Conditions
Brief summary
This study will assess the relative bioavailability of ganciclovir from the pro-drug valganciclovir in lung transplant recipients with or without cystic fibrosis. Each patient will receive 900mg valganciclovir daily for the period specified at their center, starting as soon as possible after the transplant. Pharmacokinetic assessments will be made provided that steady-state kinetics of ganciclovir and immunosuppressive drugs have been obtained (\>=4 days of drug therapy). Blood samples for pharmacokinetic analysis will be taken up to 24h post-dose on one occasion. The anticipated time on study treatment is 3-12 months, and the target sample size is \<100 individuals.
Interventions
900mg po
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* male or female patients, \>=14 years of age; * first lung or heart-lung transplant recipient; * at risk of CMV disease (D+R-,D+R+ or D-R+); * estimated creatinine clearance \>=60mL/min; * stable immunosuppressive and 900mg Valcyte dosing regimens (\>=4 days) prior to pharmacokinetic assessments.
Exclusion criteria
* history of any adverse reaction to acyclovir, valacyclovir, ganciclovir or valganciclovir; * evidence of graft rejection; * patient has received anti-CMV prophylaxis with a treatment other than cytogam, ganciclovir or valganciclovir between transplant and screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under The Observed Plasma Concentration-Time Curve Between Dosing Intervals AUC(0-tau) | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose | The area under the plasma concentration-time curve from time zero to end of dosing interval (AUC \[0-tau\]) is a measure of the plasma ganciclovir concentration from time zero to end of dosing interval. It was computed using the linear trapezoidal rule. The pharmacokinetic parameters of valganciclovir were measured in plasma of all participants following a single oral dose valganciclovir at 900 mg on Day 1. |
| Maximum Observed Plasma Concentration (Cmax) of Ganciclovir | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose | The Cmax is defined as maximum observed Ganciclovir concentration. Cmax of valganciclovir were measured in plasma of all participants following a single tablet dose Valganciclovir at 900 mg at start of treatment on Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Observed Plasma Concentration (Tmax) of Ganciclovir | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose | The Tmax is defined as time to reach maximum observed Ganciclovir concentration. The pharmacokinetic parameters of Valganciclovir were measured in plasma of all participants following a single tablet dose Valganciclovir at 900 mg at start of treatment on Day 1. |
| Apparent Elimination Rate (Kelim) of Ganciclovir | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose | The apparent elimination rate is equal to the magnitude of the slope from the log-linear regression of plasma concentration versus time over the interval t to 24, where t is the first time-point used for this regression. Kelim was not reported for those participants for whom R-squared (adjusted) was lower than 0.70. |
| Plasma Half-Life (T1/2) of Ganciclovir | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose | Plasma half-life is the time measured for the plasma concentration to decrease by one half. The pharmacokinetic parameters of Valganciclovir were measured in plasma of all participants following a single tablet dose Valganciclovir at 900 mg at start of treatment on Day 1. T1/2 was not reported for those participants for whom R-squared (adjusted) was lower than 0.70. |
Countries
United States
Participant flow
Recruitment details
A total of 31 participants were included from 5 centers in the United States of America. This study was conducted between 01 December 2004 and 30 June 2006.
Pre-assignment details
Participants were received 900 mg of commercial medication of valganciclovir tablet daily for \>= 4 days prior to study Day 1 so as to achieve steady-state kinetics of ganciclovir.
Participants by arm
| Arm | Count |
|---|---|
| Cystic Fibrosis (CF) Participants with cystic fibrosis (CF) received a single oral dose of valganciclovir 900 mg | 16 |
| Non-Cystic Fibrosis (Non-CF) Participants with non-cystic fibrosis (Non-CF) received a single oral dose of valganciclovir 900 mg | 15 |
| Total | 31 |
Baseline characteristics
| Characteristic | Cystic Fibrosis (CF) | Non-Cystic Fibrosis (Non-CF) | Total |
|---|---|---|---|
| Age, Continuous | 29.8 Years STANDARD_DEVIATION 9.82 | 51.6 Years STANDARD_DEVIATION 8.66 | 40.4 Years STANDARD_DEVIATION 14.34 |
| Sex: Female, Male Female | 10 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 16 | 4 / 15 |
| serious Total, serious adverse events | 3 / 16 | 1 / 16 |
Outcome results
Primary
Area Under The Observed Plasma Concentration-Time Curve Between Dosing Intervals AUC(0-tau)
The area under the plasma concentration-time curve from time zero to end of dosing interval (AUC \[0-tau\]) is a measure of the plasma ganciclovir concentration from time zero to end of dosing interval. It was computed using the linear trapezoidal rule. The pharmacokinetic parameters of valganciclovir were measured in plasma of all participants following a single oral dose valganciclovir at 900 mg on Day 1.
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose
Population: The Pharmacokinetic (PK) analysis population included all participants who received study medication and had at least one PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cystic Fibrosis (CF) | Area Under The Observed Plasma Concentration-Time Curve Between Dosing Intervals AUC(0-tau) | 66.2 h*mcg/mL | Standard Deviation 31.3 |
| Non-Cystic Fibrosis (Non-CF) | Area Under The Observed Plasma Concentration-Time Curve Between Dosing Intervals AUC(0-tau) | 54.1 h*mcg/mL | Standard Deviation 16.6 |
90% CI: [0.98, 1.55]
Primary
Maximum Observed Plasma Concentration (Cmax) of Ganciclovir
The Cmax is defined as maximum observed Ganciclovir concentration. Cmax of valganciclovir were measured in plasma of all participants following a single tablet dose Valganciclovir at 900 mg at start of treatment on Day 1.
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose
Population: The Pharmacokinetic (PK) analysis population included all participants who received study medication and had at least one PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cystic Fibrosis (CF) | Maximum Observed Plasma Concentration (Cmax) of Ganciclovir | 8.46 μg/mL | Standard Deviation 3.16 |
| Non-Cystic Fibrosis (Non-CF) | Maximum Observed Plasma Concentration (Cmax) of Ganciclovir | 7.54 μg/mL | Standard Deviation 2.23 |
90% CI: [0.88, 1.42]
Secondary
Apparent Elimination Rate (Kelim) of Ganciclovir
The apparent elimination rate is equal to the magnitude of the slope from the log-linear regression of plasma concentration versus time over the interval t to 24, where t is the first time-point used for this regression. Kelim was not reported for those participants for whom R-squared (adjusted) was lower than 0.70.
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose
Population: The Pharmacokinetic (PK) analysis population included all participants who received study medication and had at least one PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cystic Fibrosis (CF) | Apparent Elimination Rate (Kelim) of Ganciclovir | 4.43 1/h | Standard Deviation 0.745 |
| Non-Cystic Fibrosis (Non-CF) | Apparent Elimination Rate (Kelim) of Ganciclovir | 4.91 1/h | Standard Deviation 0.684 |
Secondary
Plasma Half-Life (T1/2) of Ganciclovir
Plasma half-life is the time measured for the plasma concentration to decrease by one half. The pharmacokinetic parameters of Valganciclovir were measured in plasma of all participants following a single tablet dose Valganciclovir at 900 mg at start of treatment on Day 1. T1/2 was not reported for those participants for whom R-squared (adjusted) was lower than 0.70.
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose
Population: The Pharmacokinetic (PK) analysis population included all participants who received study medication and had at least one PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cystic Fibrosis (CF) | Plasma Half-Life (T1/2) of Ganciclovir | 4.43 h | Standard Deviation 0.75 |
| Non-Cystic Fibrosis (Non-CF) | Plasma Half-Life (T1/2) of Ganciclovir | 4.91 h | Standard Deviation 0.68 |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) of Ganciclovir
The Tmax is defined as time to reach maximum observed Ganciclovir concentration. The pharmacokinetic parameters of Valganciclovir were measured in plasma of all participants following a single tablet dose Valganciclovir at 900 mg at start of treatment on Day 1.
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours post-dose
Population: The Pharmacokinetic (PK) analysis population included all participants who received study medication and had at least one PK sample.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cystic Fibrosis (CF) | Time to Maximum Observed Plasma Concentration (Tmax) of Ganciclovir | 1.99 h |
| Non-Cystic Fibrosis (Non-CF) | Time to Maximum Observed Plasma Concentration (Tmax) of Ganciclovir | 1.98 h |