Severe Bone Marrow Failure Due to Valganciclovir Overdose After Renal Transplantation From Cadaveric Donors: Four Consecutive Cases M. C. Ar, M. Ozbalak, N. Tuzuner, H. Bekoz, O. Ozer, K. Ugurlu, F. Tabak, and B. Ferhanoglu ABSTRACT Valganciclovir is an L-valyl ester pro-drug of ganciclovir that was initially used to treat cytomegalovirus (CMV)–associated retinitis in patients with human immunodeficiency virus. Currently, it is also indicated for the prevention of CMV disease in solid-organ transplantation. It is primarily eliminated via the kidneys through glomerular filtration and tubular secretion. Decreased renal function results in decreased drug clearance. Valgan- ciclovir has been reported to cause usually mild to moderate hematologic adverse effects such as leukopenia, neutropenia, anemia, thrombocytopenia, and pancytopenia. Severe and fatal bone marrow depression has been described in 1 adult patient. Herein, we describe the cases of 4 patients with end-stage renal disease who underwent cadaveric renal transplantation and received valganciclovir prophylaxis for CMV at a standard dose of 900 mg/d despite persistant renal failure. This therapy resulted in severe bone marrow failure after 18 to 20 days in all 4 patients, with fatal infections in 2 patients. This report demonstrates the in vivo pharmacodynamics of valganciclovir overdose in terms of hematotoxicity in the setting of renal impairment. Valganciclovir, as its derivative ganciclovir, should be used cautiously in patients with renal impairment. G ANCICLOVIR is the first drug demonstrated to be effective in life-threatening cytomegalovirus (CMV) infections. 1 Valganciclovir is an L-valyl ester pro-drug of ganciclovir with a bioavailability of approximately 60%, or as much as 10-fold higher than for oral ganciclovir. After oral administration, it is rapidly converted to ganciclovir via hydrolysis before reaching the systemic circulation. 2 Val- ganciclovir was initially used to treat CMV retinitis in patients who tested positive for human immunodeficiency virus. Currently, it is also indicated for prevention of CMV disease in high-risk patients undergoing solid-organ trans- plantation. 3–6 It is primarily eliminated via the kidneys through glomerular filtration and tubular secretion. Im- paired renal function results in decreased drug clearance, increasing its serum half-life by about 13-fold. Therefore, dose adjustment has been suggested in patients with renal dysfunction. Hemodialysis has been shown to re- duce plasma ganciclovir concentrations by about 50% after valganciclovir administration. Valganciclovir has been reported to usually cause mild to moderate hematologic adverse effects such as leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure. Data about bone marrow toxicity in valganciclovir overdose are restricted to a single adult who developed fatal bone marrow depression (medullary apla- sia) after several days of dosing that was at least 10-fold higher than the recommended dosage for the patient’s estimated degree of renal impairment. 7 Herein, we present the cases of 4 consecutive patients with end-stage renal disease who received renal transplan- tation from two cadaveric donors and developed grade 3– 4 hematotoxicity 8 (severe medullary aplasia) while receiving valganciclovir prophylaxis for CMV. From the Department of Internal Medicine (M.C.A., M.O., B.F.), Division of Hematology, Department of Pathology (N.T.), and the Department of Infectious Diseases and Clinical Microbiology (F.T.), Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey; Gayrettepe Florence Nightingale Hospital (H.B., K.U.), Istanbul, Turkey; Istanbul Pathology Group (O.O.), Istanbul, Turkey. Address reprint requests to Burhan Ferhanoglu, MD, Department of Internal Medicine, Division of Hematology, Istanbul University Cerrahpasa Medical Faculty, No:181, 34098, Kocamustafapasa - Fatih, Istanbul, Turkey. E-mail: bferhan@superonline.com 0041-1345/09/$–see front matter © 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2009.02.093 360 Park Avenue South, New York, NY 10010-1710 1648 Transplantation Proceedings, 41, 1648 –1653 (2009)