RAPID COMMUNICATION Pharmacodynamics of Oral Ganciclovir and Valganciclovir in Solid Organ Transplant Recipients Hugh Wiltshire, 1,12 Carlos V. Paya, 2 Mark D. Pescovitz, 3 Atul Humar, 4 Edward Dominguez, 5 Kenneth Washburn, 6 Emily Blumberg, 7 Barbara Alexander, 8 Richard Freeman, 9 Nigel Heaton, 10 Klaas P. Zuideveld, 11 and the Valganciclovir Solid Organ Transplant Study Group Background. A randomized, double-blind study was conducted to evaluate the pharmacokinetics of ganciclovir fol- lowing oral administration of ganciclovir or valganciclovir for prophylaxis of cytomegalovirus (CMV) disease in solid organ transplant recipients (n = 240/372). Methods. The correlations between individual exposure to ganciclovir during prophylaxis, with CMV viremia inci- dence during and after treatment, CMV disease up to 12 months posttransplant, and hematological toxicity were assessed. Results. Mean daily areas under the curve (AUCs) of ganciclovir from valganciclovir and oral ganciclovir were 46.3  15.2 and 28.0  10.9 g·h/ml (mean  SD), respectively. Viremia was suppressed during prophylaxis when exposure to ganciclovir was 40 –50 g·h/ml, AUCs typical of those achieved in valganciclovir-treated patients. The development of viremia 1 month after ending prophylaxis was also reduced with higher ganciclovir AUC (median predicted inci- dence, 20% and 10% at AUCs of 33 and 50 g h/ml, respectively). The development of CMV disease within 1 year of transplant was 17.6% and independent of prophylactic exposure to ganciclovir. There was only a weak tendency to increased neutropenia and leukopenia with higher ganciclovir exposure. Conclusions. The greater systemic exposure to ganciclovir delivered by valganciclovir was associated with delayed development of viremia. There was only a weak association between AUC and hematological toxicity. Keywords: Cytomegalovirus, Valganciclovir, Ganciclovir, Pharmacodynamics, Solid organ transplant. (Transplantation 2005;79: 1477–1483) C ytomegalovirus (CMV) is a leading cause of disease in immunocompromised subjects, including solid organ transplant (SOT) recipients (1). Ganciclovir has been the cur- rent standard of care for prevention of CMV disease and in- travenous (IV) ganciclovir is indicated for the prevention of CMV disease in at-risk transplant recipients, while the oral formulation is indicated in SOT recipients. However, IV gan- ciclovir is inconvenient for long-term use (3 months), re- quiring IV catheters and frequent home health visits (2). Oral ganciclovir was developed to offer an alternative to long-term IV therapy and is effective in SOT recipients (3–5). However, it has low bioavailability (6 –10%), which may limit the viral suppression achievable with this formulation (6) and predispose to the development of ganciclovir-resistant CMV (7). Furthermore, a dosage of 1000 mg tid as 6 –12 capsules/ day is needed to deliver plasma ganciclovir exposures that are 40 –50% of those achieved with the standard 5 mg/kg daily dosage of IV ganciclovir (2, 8). Valganciclovir is an L-valyl ester prodrug of ganciclovir that delivers ganciclovir with a bioavailability of approxi- mately 60%, up to 10-fold higher than oral ganciclovir. More- over, the convenient once-daily oral dosing regimen offered by valganciclovir provides comparable plasma ganciclovir ex- posure to that achieved with 5 mg/kg IV ganciclovir (2). A recent randomized, double-blind study showed that valganciclovir was as effective as oral ganciclovir up to 6 months posttransplant for the prevention of CMV viremia and disease in high-risk donor positive/recipient negative (D+/R-) SOT recipients (9). The aim of this study was to investigate the relationship between systemic exposure to ganciclovir and prevention of viremia, prevention of CMV disease and the occurrence of hematologic adverse events. Funding for this study was obtained from F. Hoffmann-La Roche, Basel, Switzerland. 1 Roche Products, Welwyn Garden City, Herts, UK. 2 Mayo Clinic, Rochester, MN. 3 Department of Surgery, Indiana University, Bloomington, IN. 4 Toronto General Hospital, Toronto, Ontario, Canada. 5 University of Nebraska Medical Center, Omaha, NE. 6 University of Texas Health Science Center, San Antonio, TX. 7 University of Pennsylvania Hospital, Philadelphia, PA. 8 Duke University Medical Center, Durham, NC. 9 New England Medical Center, Boston, MA. 10 Liver Transplant Department, King’s College, London, UK. 11 F. Hoffmann-La Roche, Basel, Switzerland. 12 Address correspondence to: Dr. Rene Bouw, Roche Products Ltd, 40 Broadwater Road, Welwyn Garden City, AL7 3AY E-mail: rene.bouw@roche.com Received 16 December 2004. Revision requested 11 January 2005. Accepted 7 February 2005. Copyright © 2005 by Lippincott Williams & Wilkins ISSN 0041-1337/05/7911-1477 DOI: 10.1097/01.TP.0000164512.99703.AD Transplantation • Volume 79, Number 11, June 15, 2005 1477