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Valganciclovir Dosing in Pediatric Solid Organ Transplant Recipients

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ClinicalTrials.gov Identifier: NCT02503982
Recruitment Status : Completed
First Posted : July 21, 2015
Results First Posted : June 30, 2016
Last Update Posted : April 4, 2017
Sponsor:
Information provided by (Responsible Party):
Rabin Medical Center

Tracking Information
First Submitted Date  ICMJE July 14, 2015
First Posted Date  ICMJE July 21, 2015
Results First Submitted Date  ICMJE May 23, 2016
Results First Posted Date  ICMJE June 30, 2016
Last Update Posted Date April 4, 2017
Study Start Date  ICMJE December 2014
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2017)
Area Under the Curve (AUC) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 20, 2015)
Area Under the Curve (AUC) [ Time Frame: 24 hours ]
Valganciclovir
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Valganciclovir Dosing in Pediatric Solid Organ Transplant Recipients
Official Title  ICMJE Valganciclovir Dosing in Pediatric Solid Organ Transplant Recipients - a Prospective Study
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).

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:

  1. To prospectively validate a dosing regimen of Valganciclovir 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Infection in Solid Organ Transplant Recipients
Intervention  ICMJE 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 Name: Valcyte
Study Arms  ICMJE 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.
Intervention: Drug: prophylactic Valganciclovir
Publications * Peled O, Berkovitch M, Rom E, Bilavsky E, Bernfeld Y, Dorfman L, Pappo A, Ziv-Baran T, Brandriss N, Bar-Haim A, Amir J, Ashkenazi-Hoffnung L. Valganciclovir Dosing for Cytomegalovirus Prophylaxis in Pediatric Solid-organ Transplant Recipients: A Prospective Pharmacokinetic Study. Pediatr Infect Dis J. 2017 Aug;36(8):745-750. doi: 10.1097/INF.0000000000001595.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 23, 2016)
13
Original Estimated Enrollment  ICMJE
 (submitted: July 20, 2015)
20
Actual Study Completion Date  ICMJE August 2015
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. children and adolescents 0-18 years old
  2. Solid Organ Transplantation admitted after transplantation
  3. Treatment with prophylactic Valganciclovir
  4. Glomerular Filtration Rate (GFR) >= 60 mL/min/1.73 m2

Exclusion Criteria:

  1. Treatment with ganciclovir IV
  2. Glomerular Filtration Rate (GFR) < 60 mL/min/1.73 m2
  3. Imipenem treatment
  4. Cluster organ transplanted -
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02503982
Other Study ID Numbers  ICMJE 001-14-RMC
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Rabin Medical Center
Study Sponsor  ICMJE Rabin Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Liat Ashkenazy-Hofnung, MD Schneider's Children Medical center of Isreal
PRS Account Rabin Medical Center
Verification Date April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP