Clinical trial NCT02503982: Valganciclovir Dosing in Pediatric Solid Organ Transplant Recipients
Official title: Valganciclovir Dosing in Pediatric Solid Organ Transplant Recipients - a Prospective Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Infection in Solid Organ Transplant Recipients
Lead sponsor: Rabin Medical Center
Sponsor class: OTHER
First posted: 2015-07-21
Enrollment: 13
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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 Blood was withdrawn at steady state: 2, 5 and 10 hours post dosing.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.

Eligibility criteria: 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 -

Primary outcomes:
measure: Area Under the Curve (AUC)
timeFrame: drug levels measured at 2, 5 and 10 h following administration of the dose on day 4 creating a 24 hours curve
Secondary outcomes:
Other outcomes:
Locations:
city: Petah Tikva
country: Israel
facility: Schneider childrens medical center of Isreal
Study officials:
affiliation: Schneider's Children Medical center of Isreal
name: Liat Ashkenazy-Hofnung, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.