Electronic Estimations of Renal Function Are Inaccurate in Solid-Organ Transplant Recipients and Can Result in Significant Underdosing of Prophylactic Valganciclovir

Abstract

e In a prospective study of solid-organ transplant recipients (n ‫؍‬ 22; 15 hepatic and 7 renal) receiving valganciclovir for cytomegalovirus (CMV) prophylaxis, electronic estimation of glomerular filtration rate (eGFR) underestimated the true GFR (24-h urine creatinine clearance) by >20% in 14/22 (63.6%). Its use was associated with inappropriate underdosing of valganciclovir, while the Cockroft-Gault equation was accurate in 21/22 patients (95.4%). Subtherapeutic ganciclovir levels (<0.6 mg/liter) were common, occurring in 10/22 patients (45.4%); 7 had severely deficient levels (<0.3 mg/liter).

Systematic review of ganciclovir pharmacodynamics during the prevention of cytomegalovirus infection in adult solid organ transplant recipients

“…Trevillyan et al conducted a prospective study measuring trough GCV concentrations in 22 renal or hepatic transplant recipients receiving ValGCV prophylaxis for 3 to 6 months (Table ). High‐risk participants were recommended 6 months of ValGCV.…”

“…At present, GCV and ValGCV dosing decisions are not routinely informed by use of a therapeutic range. The target cut‐offs for C min vary across different laboratories and range between 0.06 and 2.5 μg/mL in human organ and tissue transplant studies . The dose‐dependent inhibition of human CMV replication by GCV has been established in vitro, with a reported 50% inhibitory concentration of 1.5 μg/mL …”

“…Clinical drug level monitoring of free GCV in plasma or serum samples is often used in studies as a surrogate for intracellular GCV triphosphate, which is the active component of the drug. Suboptimal GCV blood concentrations during treatment for CMV infection result from (1) hemodialysis where ~50% of the administered GCV was eliminated from the plasma after 4 hours of dialysing, (2) use of an inappropriate dosing algorithm, and (3) inaccurate estimation of glomerular filtration rate (GFR) . Suboptimal GCV concentrations may promote the emergence of resistant CMV strains .…”

Underdosing of Prophylactic Valganciclovir Due to Inaccurate Estimation of Glomerular Filtration Rate Leading to Severe Cytomegalovirus Disease in a Kidney Transplant Recipient

“…In clinical practice, however, the estimated GFR (eGFR) is commonly calculated with the modification of diet in renal disease (MDRD) equation instead (5), as it can easily be provided by the clinical laboratory. In a recent paper by Trevillyan et al, it was shown that dosing valganciclovir based on the eGFR as computed with the MDRD equation may lead to underdosing of valganciclovir in a substantial number of solid-organ transplant recipients (6). We fully agree with the authors that this may have major clinical implications, especially since viral load monitoring during prophylactic valganciclovir therapy is not routinely performed (4), due to the low antiviral resistance to the drug and high costs.…”

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“…19,20 As advised in the literature and by the manufacturer, the Cockcroft-Gault formula is considered an appropriate and practical method to estimate GFR to decide for valganciclovir dose. [19][20][21] Cytomegalovirus disease resistance has been reported as a result of lower valganciclovir dose given after underestimation of GFR by Modification of Diet in Renal Disease formula, which responded well after adjustment of the valganciclovir dose to the Cockcroft-Gault formula. 22 In a multivariate analysis, 12 trials with 900 mg valganciclovir (1543 patients) and 8 trials with 450 mg valganciclovir (1531 patients) were included.…”