Population Pharmacokinetics of Ganciclovir in Allogeneic Hematopoietic Stem Cell Transplant Patients

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 (CL_CR) 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 CL_CR 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 CL_CR estimated by CKD-EPI. Incorporation of loading doses into induction dosing regimens should be considered for timely achievement of currently suggested exposures.

Keywords: allogeneic haematopoietic stem cell transplantation; cytomegalovirus; ganciclovir; pharmacokinetics; valganciclovir.

FIG 1

Observed-versus-predicted goodness-of-fit plots for total ganciclovir concentration.

FIG 2

(a–h) Probability of target attainment of efficacy (AUC24 > 80) and toxicity (AUC24 < 120) on day 7 of ganciclovir induction therapy in patients with different creatinine clearances estimated by the BSA-adjusted CKD-EPI equation and on CRRT (continuous renal replacement therapy). The shaded area indicates the difference between the efficacy and the toxicity probability.

FIG 3

(a–h) Probability of target attainment of efficacy (AUC24 > 40) and toxicity (AUC24 < 60) on day 7 of ganciclovir maintenance therapy in patients with different creatinine clearances estimated by the BSA-adjusted CKD-EPI equation and on CRRT (continuous renal replacement therapy). The shaded area indicates the difference between the efficacy and the toxicity probability.