PP215—Pharmacokinetic Study of Ganciclovir (GCV) After Single and Multiple Dose in Hematopoietic Stem Cell Transplant (Hsct) Patients with Cytomegalovirus (CMV) Infection

Abstract

Pharmacokinetic data of GCV are limited in HSCT patients under preemptive therapy and its induced hematologic toxicity still problematic.The aim of this study was to evaluate the PK of GCV after single and multiple doses in HSCT patients with CMV infection and to identify correlation between PK parameters and hematologic toxicity. A PK study was conducted between October 2008 and December 2009 at MG hospital in Beirut, after IV GCV treatment in HSCT recipients with CMV infection. CMV disease was recognized by the combination of clinical signs and antigenemia. Patients received 1-hour infusion of 5 mg/kg q 12h for 14 days, and a complete PK study was performed at days 1, 7, and 14. A compartmental and no PK analysis were performed, and plasma GCV was analyzed by an HPLC validated method with UV detection. An ANOVA analysis associated to Freadman test was performed to compare the mean PK parameters. The 95% CI was calculated for some parameters and P < 0.05 was considered significant. Twelve patients were enrolled in this study. A significant difference in creatinine clearance (Clcr) and trombecytopenia, occurred between days 1, 7, and 14 (P < 0.0001, P = 0.008, respectively). Mean peak concentrations (Cmax) was 9.4 (2.7) μ/mL (95% CI, 7.3–11.4) and decreased according to the bicompartmental model, without any significant accumulation during 14 days of treatment. Mean minimal concentration were well above the CI50 needed to inhibit human CMV. The plasma concentrations were not correlated with hematologic effects, indicating that the dosage of intracellular GCV is needed to explain this induced‐toxicity. The mean half‐life of elimination (t½β) was 6.4 (2) hours, and the total clearance of DHPG (CLGCV, 139 [20.4] mL/min) was greater and linearly correlated to CLcr (r = 0.930; P < 0.0008). The apparent volume of distribution (Vdβ) was (1.2 [0.32] L/kg) higher than that reported to the Solid Organ Transplant patients. At steady‐state, an inter‐ and intra‐patient variability were observed for CLGCV, t½β, and Vdβ suggesting the presence of a subgroup patient. A population PK should be tested in the future studies to identify the best predictor parameter for dosage adjustment to improving the most efficacious GCV exposure.