Valganciclovir Dosing in Pediatric Solid Organ Transplant Recipients

Infection in Solid Organ Transplant Recipients Clinical Trial

Official title:

Valganciclovir Dosing in Pediatric Solid Organ Transplant Recipients - a Prospective Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02503982
• Other study ID #: 001-14-RMC
• Status: Recruiting
• Phase: Phase 4
• First received: July 14, 2015
• Last updated: July 20, 2015
• Start date: December 2014
• Est. completion date: December 2016

Study information

• Verified date: June 2015
• Source: Rabin Medical Center
• Contact: Liat Ashkenazy-Hofnung, MD
• Phone: +972-54-4749345
• Email: LiatA3[@]clalit.org.il
• Is FDA regulated: No
• Health authority: Israel: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

Valganciclovir (VGC) is extensively used for cytomegalovirus (CMV) infection treatment and prophylaxis after solid organ transplantation (SOT). VGC dosing is problematic in children. VGC 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 VGC 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 Blood was withdrawn at steady state: 2, 5 and 10 hours post dosing.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).

Description:

Valganciclovir (VGC) 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 (GCV), has a bioavailability of approximately 60%, which is up to 10-fold higher than oral GCV.

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 VGC, 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:

1. To prospectively validate a dosing regimen of VGC administration

2. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: December 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 20 Years

Eligibility

Inclusion Criteria:

1. children and adolescents 0-20 years old

2. Solid Organ Transplantation admitted after transplantation

3. Treatment with prophylactic Valganciclovir

Exclusion Criteria:

1. Treatment with ganciclovir IV

2. Glomerular Filtration Rate (GFR) < 25 mL/min/1.73 m2

3. Imipenem treatment

4. Cluster organ transplanted -

Study Design

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Infection in Solid Organ Transplant Recipients

Intervention

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.

Locations

Country	Name	City	State
Israel	Schneider childrens medical center of Isreal	Petah Tikva

Sponsors (1)

Lead Sponsor	Collaborator
Rabin Medical Center

Country where clinical trial is conducted

Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Curve (AUC)	Valganciclovir	24 hours	No