Body Surface Area Valganciclovir Prophylactic Dosing is Associated with a Higher Rate of Drug-Associated Toxicities Compared to Body Weight Dosing in Pediatric Solid Organ Transplant Recipients
Authors: Demirhan Salih , Munoz Flor M , Valencia Deray Kristen G , Bocchini Claire E , Danziger-Isakov Lara , Blum Samantha , Sharma Tanvi S , Sherman Gilad , Boguniewicz Juri , Bacon Samantha , Ardura Monica I , Maron Gabriela M , Ferrolino Jose , Foca Marc , Herold Betsy C 
Published: November 2023

Abstract

Background
Valganciclovir (VGCV) is used for prevention of cytomegalovirus (CMV) in pediatric solid organ transplant (SOT) recipients who are at moderate or high risk for CMV infection or reactivation. Optimal dosing is not well defined, and both weight-based (WB) (15 mg/kg/dose) and body surface area-based (BSA) dosing (7 x BSA x creatinine clearance with an upper limit of 150 mL/min/1.73 m2) are used. We used a recently completed retrospective study on VGCV toxicity to compare the effects of these 2 dosing strategies on the proportion and the odds of CMV DNAemia, neutropenia, lymphopenia, and toxicity-related VGCV discontinuation or dose modification.

Methods
Data was collected from 6 US centers. Inclusion criteria were SOT recipients &lt;20 years of age transplanted between January 2016 and December 2019, anticipated to receive VGCV prophylaxis with either dosing method for &gt;/=3 months, and availability of &gt;/=6 months of follow-up data post-transplant. Neutropenia and lymphopenia were defined as absolute neutrophil or lymphocyte count &lt;1000 cells/microL. The number of patients who had premature discontinuation or dosing modification attributed to leukopenia or acute kidney injury (AKI) was quantified. Anticipated VGCV duration, dosing strategy, and threshold for making VGCV changes were at the discretion of each center for each patient. Cytopenias or toxicities that occurred within 15 days of SOT were excluded. Data were collected for one-year post-transplant and analyzed using Stata version 17.0. Groups were compared using Mann Whitney U test for continuous variables and chi-square test for categorical variables; logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) with multivariable analysis.

Results
412 patients met inclusion criteria. 312 patients were treated with WB and 100 with BSA dosing. Median age at transplantation was 5.1 (IQR 1.8-11.8) years and 42.7% were female. Transplanted organs included: liver 35.4%, kidney 33.5%, heart 22.3%, lung 6.6%, and other 2.2%. Within one year of transplantation, 23.4% and 12.2% of the WB group and 31.0% and 16% of the BSA group had at least one episode of CMV DNA detection in the plasma (DNAemia) and breakthrough CMV DNAemia while on VGCV prophylaxis, respectively (p=0.1 and p=0.3). There was no statistically significant difference in the odds of CMV DNAemia or breakthrough CMV DNAemia between dosing groups at one year when adjusted for: transplanted organ, CMV risk based on pre-transplant serostatus, duration of anticipated prophylaxis, age, receipt of CMV immunoglobulin, anti-thymocyte globulin, basiliximab, alemtuzumab, mycophenolate and corticosteroid (aOR=1.1, 95% CI: 0.6-1.8, p=0.8 and aOR=1.4, 95% CI: 0.6-2.9, p=0.4). However, the risk of all drug toxicity while on prophylaxis were significantly greater in BSA compared to WB group: neutropenia (50.0% vs 29.3%), lymphopenia (51.0% vs 15.0%), and toxicity-related VGCV discontinuation or modification (21% vs 6.7%) (each p&lt;0.001). The BSA group had higher odds of neutropenia (aOR=2.3, 95% CI: 1.4-3.7, p=0.001), lymphopenia (aOR=7.0, 95% CI: 3.9-12.4, p&lt;0.001), and toxicity-related VGCV discontinuation or modification (aOR=4.6, 95% CI: 2.2-9.3, p&lt;0.001) while on prophylaxis when adjusted for age, organ, anticipated VGCV duration, and receipt of trimethoprim-sulfamethoxazole, anti-thymocyte globulin, basiliximab, alemtuzumab, mycophenolate and corticosteroid.

Conclusions
Results of this study indicate that BSA dosing of VGCV is associated with a significantly greater risk of toxicity without a decrease in CMV DNAemia.