Trough ganciclovir concentration as predictor of leukopenia in lung transplant recipients receiving valganciclovir prophylaxis

Abstract

BackgroundValganciclovir is the first‐line agent for Cytomegalovirus prophylaxis after lung transplantation. However, its use is associated with a relatively high risk of hematological toxicity. This study aimed to investigate the relationship between trough ganciclovir concentration and hematologic toxicity in lung transplantation patients receiving valganciclovir prophylaxis, and identify factors that affect ganciclovir pharmacokinetics in this population.MethodsThis prospective observational study included 24 lung transplant patients receiving valganciclovir prophylaxis. The cutoff value of trough ganciclovir concentration was estimated using receiver operating characteristic analysis in leukopenia grade 3 and higher. Population pharmacokinetic analysis was performed using a nonlinear mixed‐effects modeling program.ResultsThe trough ganciclovir concentration was significantly higher in the group with leukopenia grades 3 or higher than in the group with grades less than or equal to 2 (1605.7 ± 860.1 ng/mL [n = 3] vs. 380.5 ± 175.8 ng/mL (n = 21), p < .001). The cutoff value of trough ganciclovir concentration for predicting greater than or equal to grade 3 leukopenia was estimated as 872.0 ng/mL. Creatinine clearance and lung re‐transplantation were found to have a significant impact on the total body clearance of valganciclovir. Ganciclovir clearance was decreased in patients with reduced creatine clearance or re‐transplantation.ConclusionThese results suggest that higher ganciclovir trough concentrations are associated with an increased risk of leukopenia grade 3 or higher, and that creatinine clearance and lung re‐transplantation affected the pharmacokinetics of ganciclovir. image

A case of successful contribution of therapeutic drug monitoring of valganciclovir as the prophylaxis against cytomegalovirus infection in a lung transplant recipient

“…In this case, the initial valganciclovir dosage was established considering renal function; nevertheless, the patient encountered a decline in the white blood cell count to 2,220/μL. The results of our previous study suggested that a ganciclovir trough concentration of 872 ng/ mL or higher is associated with severe leukopenia [9]. We adjusted the valganciclovir dosage based on the trough serum concentrations of ganciclovir and successfully administered it without CMV reactivation or significant adverse effects.…”

“…The patient experienced continuous post-hemodiafiltration withdrawal and exhibited relatively impaired renal function, leading us to hypothesize that this condition might delay ganciclovir excretion and heighten the risk of severe leukopenia. To avoid cessation of valganciclovir prophylaxis, we performed TDM to maintain trough concentrations of ganciclovir below 872 ng/mL, which is less toxic than that previously reported by our group [9]. Serum ganciclovir concentrations were measured using liquid chromatography-tandem mass spectrometry as described previously [9].…”

“…To avoid cessation of valganciclovir prophylaxis, we performed TDM to maintain trough concentrations of ganciclovir below 872 ng/mL, which is less toxic than that previously reported by our group [9]. Serum ganciclovir concentrations were measured using liquid chromatography-tandem mass spectrometry as described previously [9]. The lower limit of quantification of ganciclovir using this method was 100 ng/mL.…”

“…For this case, the target trough concentration range for ganciclovir was established at 300-800 ng/mL following consultations with infectious disease specialists and pharmacists to mitigate the risk of toxicity. Although the prophylactic target concentration range of GCV has not been established, it was anticipated, based on our previous study [9], that maintaining the trough blood concentration of GCV above 300 ng/mL would prevent CMV reactivation. The trough concentration of ganciclovir was 1,235 ng/mL on POD 64 and 963 ng/mL on POD 68.…”

“…Nevertheless, there are no established guidelines for optimal serum ganciclovir levels for prophylaxis of CMV infection. Although the threshold trough ganciclovir concentration associated with toxicity has not been fully elucidated, our group previously reported that a trough ganciclovir concentration of ≥ 872 ng/mL resulted in grade 3 or higher leukopenia in lung transplant recipients receiving valganciclovir prophylaxis [9]. Despite these findings, TDM of ganciclovir has not yet been implemented in clinical practice.…”