Comparison of Three Renal Function Formulas for Ganciclovir/Valganciclovir Dose Individualization in CMV-Infected Solid Organ Transplantation Patients Using a Population Approach

Background and Objective The gold standard treatment of established cytomegalovirus infection or prevention in solid organ transplantation is the intravenous administration of ganciclovir (GCV) or oral administration of valganciclovir (VGCV), both adjusted to the renal function. In both instances, t...

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Published in:Clinical pharmacokinetics 2023-06, Vol.62 (6), p.861-880
Main Authors: Lalagkas, Panagiotis Nikolaos, Iliou, Jorge, Rigo, Raul, Miarons, Marta, Fernández-Alarcon, Beatriz, Bestard, Oriol, Cruzado, Josep M., Melilli, Edoardo, Torras, Joan, Grinyó, Josep M., Lloberas, Nuria, Colom, Helena
Format: Article
Language:English
Subjects:
Antiviral Agents - pharmacokinetics
Clinical medicine
Collaboration
Creatinine
Cytomegalovirus
Cytomegalovirus Infections - drug therapy
Cytomegalovirus Infections - prevention & control
Disease prevention
Drug dosages
Epidemiology
Ganciclovir - pharmacokinetics
Ganciclovir - therapeutic use
Humans
Infections
Internal Medicine
Kidney - physiology
Kidney diseases
Medicine
Medicine & Public Health
Optimization
Oral administration
Organ Transplantation
Original
Original Research Article
Patients
Pharmacokinetics
Pharmacology/Toxicology
Pharmacotherapy
Renal Insufficiency, Chronic - drug therapy
Transplants & implants
Valganciclovir
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Summary:Background and Objective The gold standard treatment of established cytomegalovirus infection or prevention in solid organ transplantation is the intravenous administration of ganciclovir (GCV) or oral administration of valganciclovir (VGCV), both adjusted to the renal function. In both instances, there is a high interindividual pharmacokinetic variability, mainly owing to the wide range of variation of both the renal function and body weight. Therefore, accurate estimation of the renal function is crucial for GCV/VGCV dose optimization. This study aimed to compare three different formulas for estimating the renal function in solid organ transplantation patients with cytomegalovirus infection, for individualizing antiviral therapy with GCV/VGCV, using a population approach. Methods A population pharmacokinetic analysis was performed using NONMEM 7.4. A total of 650 plasma concentrations obtained after intravenous GCV and oral VGCV administrations were analyzed, from intensive and sparse sampling designs. Three different population pharmacokinetic models were built with the renal function given by Cockcroft–Gault, Modification of Diet in Renal Disease, or Chronic Kidney Disease EPIdemiology Collaboration (CKD-EPI) formulas. Pharmacokinetic parameters were allometrically scaled to body weight. Results The CKD-EPI formula was identified as the best predictor of between-patient variability in GCV clearance. Internal and external validation techniques showed that the CKD-EPI model had better stability and performed better compared with the others. Conclusions The model based on the more accurate estimation of the renal function with the CKD-EPI formula and body weight as a size metric most used in the clinical practice can refine initial dose recommendations and contribute to GCV and VGCV dose individualization when required in the prevention or treatment of cytomegalovirus infection in solid organ transplantation patients. Graphical Abstract
ISSN:0312-5963
1179-1926
DOI:10.1007/s40262-023-01237-3