Population Pharmacokinetics of Ganciclovir in Allogeneic Hematopoietic Stem Cell Transplant Patients
Date
2023
Authors
Selby, P.R.
Heffernan, A.J.
Yeung, D.
Warner, M.S.
Peake, S.L.
Hahn, U.
Wallis, S.C.
Mcwhinney, B.
Ungerer, J.P.J.
Shakib, S.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Antimicrobial Agents and Chemotherapy, 2023; 67(3):e0155022-e0155022
Statement of Responsibility
Philip R. Selby, Aaron J. Heffernan, David Yeung, Morgyn S. Warner, Sandra L. Peake, Uwe Hahn, Steven C. Wallis, Brett Mcwhinney, Jacobus P. J. Ungerer, Sepehr Shakib, Jason A. Roberts
Conference Name
Abstract
Treatment of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (alloHCT) patients with ganciclovir is complicated by toxicity and resistance. This study aimed to develop an intravenous ganciclovir population pharmacokinetic model for post-alloHCT patients and to determine dosing regimens likely to achieve suggested therapeutic exposure targets. We performed a prospective observational single-center pharmacokinetic study in adult alloHCT patients requiring treatment with intravenous ganciclovir for CMV viremia or disease. Samples were analyzed using a validated ultraperformance liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. Twenty patients aged 18 to 69 years were included in the study. A 2-compartment model with linear elimination from the central compartment and between occasion variability best described the data. Incorporating creatinine clearance (CLCR) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and presence of continuous renal replacement therapy as covariates for ganciclovir clearance improved the model. Compared to current dosing recommendations, simulations demonstrated loading doses were required to achieve a target AUC24 of 80 to 120 mg.h/L on day 1 of induction therapy. Increased individualization of post-loading induction and maintenance doses based on CLCR is required to achieve the suggested exposures for efficacy (AUC24 >80/>40 mg.h/L for induction/maintenance) while remaining below the exposure thresholds for toxicity (AUC24 <120/<60 mg.h/L for induction/maintenance). Intravenous ganciclovir dosing in alloHCT patients can be guided by CLCR estimated by CKD-EPI. Incorporation of loading doses into induction dosing regimens should be considered for timely achievement of currently suggested exposures.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2023 American Society for Microbiology. All Rights Reserved