Valganciclovir Dosing in Pediatric Solid Organ Transplant Recipients
Study Details
Study Description
Brief Summary
Valganciclovir is extensively used for cytomegalovirus (CMV) infection treatment and prophylaxis after solid organ transplantation (SOT). VGC dosing is problematic in children. valganciclovir has variable absorption and is renally excreted. Area Under the Curve (AUC) (0-24) of 40-60 mcg∙h/L is a predictive pharmacokinetic parameter of efficacy and safety. Dosing based on manufacturer recommendations is supra-therapeutic in most cases. A few published dosing algorithms result in AUC out of range.
Objective: To prospectively validate a Valganciclovir administration dosing regimen and compare it to other dosing algorithms.
Methods: Children after SOT at Schneider Children's Medical Center, the largest tertiary pediatric center in Israel, were prospectively studied, starting Dec 2014. The dosing regimen was derived from Seattle Children's Hospital guidelines; 14-16 mg/kg/dose. For impaired renal function, stratified dose reduction was used. Blood was withdrawn at steady state: 2, 5 and 10 hours post dosing. Drug level was analyzed by high pressure liquid chromatography (HPLC).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
Valganciclovir is a novel drug used extensively as a prophylactic, preemptive and treatment agent for cytomegalovirus (CMV) infection after solid organ transplantation (SOT).
It is the valine ester prodrug of Ganciclovir,has a bioavailability of approximately 60%, which is up to 10-fold higher than oral ganciclovir .
Based on the correlation between the Pharmacokinetic (PK) of VGC and its clinical efficacy found in adult studies, AUC (0-24) of approximately 40-60 mcg∙h/mL has been described as predictive PK parameter of efficacy. Considering the mechanism of action of Valganciclovir , relationships of exposure-efficacy and exposure-safety are expected to be similar in children and adults.
In 2009, a new dosing algorithm incorporating both body surface area (BSA) and renal function was introduced by the manufacturer for infants and young children:
Dose (mg) =7 × BSA × CrCl
Very few studies have evaluated this dosing for infants and young children. In 2010 the FDA published a safety alert confirming the excessively high dosage calculated by the dosing algorithm in children with low body weight, low body surface area, and normal serum creatinine. This type of patient was not routinely observed in the clinical trials used to derive and confirm the pediatric dose.
As the body weight decreases and/or as the Creatinine Clearance (CrCl) increases excessively high doses are calculated. There is unproportional variability of doses calculated by the algorithm for infants and young children with normal renal function.
Doses can reach as high as 4 fold higher than the weight-based common dosing.
Objective:
-
To prospectively validate a dosing regimen of Valganciclovir administration
-
and to compare it to other dosing algorithms.
Methods:
This is a prospective study of all pediatric SOT recipients who were treated with oral valganciclovir. The common practice dose at Schneider Children's Medical Center dosing guidelines of valganciclovir is 17 mg/kg once daily for prophylaxis, with stratified dose reductions for impaired renal function as shown in the table. Max dose was 900 mg.
Measurement of valganciclovir levels After three days of consistent oral dosing to ensure steady-state concentrations, drug levels were measured at 2, 5 and 10 h following administration of the dose, and were analyzed at the pharmacologic laboratory of "Asaf HaRofeh Medical Center" using standard HPLC, with a lower limit of detection of 0.5 mcg/mL and a coefficient of variation of <10%. AUCs were calculated using the trapezoidal method.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Solid Organ Transplanted children Intervention: treatment with prophylactic oral valganciclovir with a fixed dose of 17 mg/kg once daily for prophylaxis, and stratified dose reductions for impaired renal function. Max dose was 900 mg. |
Drug: prophylactic Valganciclovir
The common practice dose at Schneider Children's Medical Center dosing guidelines of valganciclovir is 17 mg/kg once daily for prophylaxis, with stratified dose reductions for impaired renal function. Max dose was 900 mg.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Area Under the Curve (AUC) [drug levels measured at 2, 5 and 10 h following administration of the dose on day 4 creating a 24 hours curve]
Valganciclovir area under the curve (AUC) calculated with the trapezoidal method using drug levels measured at 2, 5 and 10 h, and extrapolated beyond the 10 hour time point to arrive at a 24-hour curve.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
children and adolescents 0-18 years old
-
Solid Organ Transplantation admitted after transplantation
-
Treatment with prophylactic Valganciclovir
-
Glomerular Filtration Rate (GFR) >= 60 mL/min/1.73 m2
Exclusion Criteria:
-
Treatment with ganciclovir IV
-
Glomerular Filtration Rate (GFR) < 60 mL/min/1.73 m2
-
Imipenem treatment
-
Cluster organ transplanted -
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Schneider childrens medical center of Isreal | Petah Tikva | Israel |
Sponsors and Collaborators
- Rabin Medical Center
Investigators
- Principal Investigator: Liat Ashkenazy-Hofnung, MD, Schneider's Children Medical center of Isreal
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 001-14-RMC
Study Results
Participant Flow
| Recruitment Details | conducted at the Schneider Children's Medical Center (SCMC) from December 2014 to August 2015. |
|---|---|
| Pre-assignment Detail | A prospective pharmacokinetic. age <18 years of age, GFR>60 mL/min/1.73m2, solid-organ transplantation and oral VGC prophylaxis for CMV infection |
| Arm/Group Title | Solid Organ Transplanted Children |
|---|---|
| Arm/Group Description | Intervention: treatment with prophylactic oral valganciclovir with a fixed dose of 17 mg/kg once daily for prophylaxis. Max dose was 900 mg. prophylactic Valganciclovir: The common practice dose at Schneider Children's Medical Center dosing guidelines of valganciclovir is 17 mg/kg once daily for prophylaxis. Max dose was 900 mg. |
| Period Title: Overall Study | |
| STARTED | 13 |
| COMPLETED | 13 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Solid Organ Transplanted Children |
|---|---|
| Arm/Group Description | Intervention: treatment with prophylactic oral valganciclovir with a fixed dose of 17 mg/kg once daily for prophylaxis. Max dose was 900 mg. prophylactic Valganciclovir: The common practice dose at Schneider Children's Medical Center dosing guidelines of valganciclovir is 17 mg/kg once daily for prophylaxis. Max dose was 900 mg. |
| Overall Participants | 13 |
| Age (Count of Participants) | |
| <=18 years |
13
100%
|
| Between 18 and 65 years |
0
0%
|
| >=65 years |
0
0%
|
| Age (years) [Median (Inter-Quartile Range) ] | |
| Median (Inter-Quartile Range) [years] |
7.3
|
| Sex: Female, Male (Count of Participants) | |
| Female |
4
30.8%
|
| Male |
9
69.2%
|
Outcome Measures
| Title | Area Under the Curve (AUC) |
|---|---|
| Description | Valganciclovir area under the curve (AUC) calculated with the trapezoidal method using drug levels measured at 2, 5 and 10 h, and extrapolated beyond the 10 hour time point to arrive at a 24-hour curve. |
| Time Frame | drug levels measured at 2, 5 and 10 h following administration of the dose on day 4 creating a 24 hours curve |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Solid Organ Transplanted Children |
|---|---|
| Arm/Group Description | Intervention: treatment with prophylactic oral valganciclovir with a fixed dose of 17 mg/kg once daily for prophylaxis. Max dose was 900 mg. prophylactic Valganciclovir: The common practice dose at Schneider Children's Medical Center dosing guidelines of valganciclovir is 17 mg/kg once daily for prophylaxis. Max dose was 900 mg. |
| Measure Participants | 13 |
| Median (Inter-Quartile Range) [mcg∙h/mL] |
21.0
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Solid Organ Transplanted Children | |
| Arm/Group Description | Intervention: treatment with prophylactic oral valganciclovir with a fixed dose of 17 mg/kg once daily for prophylaxis. Max dose was 900 mg. prophylactic Valganciclovir: The common practice dose at Schneider Children's Medical Center dosing guidelines of valganciclovir is 17 mg/kg once daily for prophylaxis. Max dose was 900 mg. | |
All Cause Mortality |
||
| Solid Organ Transplanted Children | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Solid Organ Transplanted Children | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/13 (23.1%) | |
| Blood and lymphatic system disorders | ||
| Hematologic toxicity | 3/13 (23.1%) | 3 |
Other (Not Including Serious) Adverse Events |
||
| Solid Organ Transplanted Children | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/13 (0%) | |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Liat Ashkenazi-Hoffnung |
|---|---|
| Organization | Schneider Children's Medical Center of Israel |
| Phone | 972-3-9253681 |
| LiatA3@clalit.org.il |
- 001-14-RMC