Pharmacokinetic Profile of Ganciclovir After its Oral Administration and From its Prodrug, Valganciclovir, in Solid Organ Transplant Recipients
Valganciclovir (Valcyte/sR) has recently been approved for the prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+1/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.
The pharmacokinetics of ganciclovir from oral ganciclovir (Cymevene®, lOOOmg 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.
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 μg · h/mL and 28.0 ± 10.9 μg · 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 μg · h/mL, respectively). Adherence to the prescribed dosing regimens, which were reduced for renal impairment, gave consistent exposure to ganciclovir.
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.
This study was funded by Hoffman-La Roche Ltd, Basel, Switzerland. Hugh Wiltshire is an employee of the sponsor. Mark Pescovitz has received honoraria for speaking and is a consultant to the sponsor. Atul Humar is a consultant for the sponsor. Barbara Alexander, Emily Blumberg and Richard Freeman have received honoraria for speaking for the sponsor.
- 17.Beal SL, Boeckmann A, Sheiner LB. NONMEM users guide (Pt 1): VIII. San Franscisco (CA): NONMEM Project Group C255, University of California at San Francisco, 1988–1998Google Scholar
- 19.Beal SL, Sheiner LB. NONMEM users guides. San Francisco (CA): NONMEM Project Group, University of California, 1992Google Scholar
- 28.Paladino JA, Kapfer JA, DiBona JR. Bedside estimation of Creatinine clearance: which method is most accurate while least complex? Hosp Formul 1986; 21: 709–15Google Scholar