Pharmacokinetic Profile of Ganciclovir After its Oral Administration and From its Prodrug, Valganciclovir, in Solid Organ Transplant Recipients

Authors: Wiltshire, Hugh¹; Hirankarn, Sarapee²; Farrell, Colm²; Paya, Carlos³; Pescovitz, Mark D.⁴; Humar, Atul⁵; Dominguez, Edward⁶; Washburn, Kenneth⁷; Blumberg, Emily⁸; Alexander, Barbara⁹; Freeman, Richard¹⁰; Heaton, Nigel¹¹

Source: Clinical Pharmacokinetics, Volume 44, Number 5, 2005 , pp. 495-507(13)

Publisher: Adis International

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Abstract:

Background: Valganciclovir (Valcyte^®) has recently been approved for the prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negative [R–]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are lacking. A recent randomised, double-blind study of valganciclovir in 364 D+/R– (intent-to-treat population) SOT recipients provided valuable data on which a population pharmacokinetic analysis was performed.

Methods: The pharmacokinetics of ganciclovir from oral ganciclovir (Cymevene^®, 1000mg three times daily) and from valganciclovir (900mg once daily) were described with plasma levels from 240 patients (1181 datapoints describing 449 pharmacokinetic profiles) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment pharmacokinetic model with separate absorption/metabolism and absorption parameters for valganciclovir and ganciclovir, respectively, was developed.

Results: Exposure to ganciclovir from valganciclovir averaged 1.65-fold greater than that from oral ganciclovir (95% CI 1.58, 1.81); respective daily area under the plasma concentration-time curve values were 46.3 ± 15.2

g · h/mL and 28.0 ± 10.9

g · h/mL. The relative systemic exposure of ganciclovir was approximately 8-fold higher from valganciclovir than oral ganciclovir. Exposure to ganciclovir from valganciclovir was similar among liver, heart and kidney transplant recipients (46.0 ± 16.1, 40.2 ± 11.8 and 48.2 ± 14.6

g · h/ mL, respectively). Adherence to the prescribed dosing regimens, which were reduced for renal impairment, gave consistent exposure to ganciclovir.

Conclusion: Oral valganciclovir produces exposures of ganciclovir exceeding those attained with oral ganciclovir, but in line with those reported after standard intravenous administration of ganciclovir. This indicates that oral valganciclovir is suitable in circumstances requiring prophylactic use of ganciclovir and allows for more convenient management of patients at risk of CMV disease.

Keywords: Ganciclovir; Valganciclovir; Antivirals; DNA polymerase inhibitors; Nucleosides; Transplantation

Document Type: Research article

Affiliations: 1: 1 Roche Products Ltd, Welwyn Garden City, UK 10: 10 New England Medical Center, Boston, Massachusetts, USA 11: 11 King's College, London, UK 2: 2 GloboMax – a division of ICON plc., Marlow, UK 3: 3 Mayo Clinic, Rochester, New York, USA 4: 4 Departments of Surgery/Microbiology/Immunology, Indiana University, Indianapolis, Indiana, USA 5: 5 Toronto General Hospital, Toronto, Ontario, Canada 6: 6 University of Nebraska Medical Center, Omaha, Nebraska, USA 7: 7 University of Texas Health Science Center, San Antonio, Texas, USA 8: 8 Hospital of the University of Pennsylvania, Philadelphia, Pennsylvannia, USA 9: 9 Duke University Medical Center, Durham, North Carolina, USA

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