title: Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients.
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, 1000 mg three times daily) and from valganciclovir (900 mg 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 microg . h/mL and 28.0 +/- 10.9 microg . 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 microg . h/ mL, respectively). Adherence to the prescribed dosing regimens, which were reduced for renal impairment, gave consistent exposure to ganciclovir.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Roche Products Ltd, Welwyn Garden City, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Wiltshire
authors.forename: Sarapee
authors.initials: S
authors.lastname: Hirankarn
authors.forename: Colm
authors.initials: C
authors.lastname: Farrell
authors.forename: Carlos
authors.initials: C
authors.lastname: Paya
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pescovitz
authors.forename: Atul
authors.initials: A
authors.lastname: Humar
authors.forename: Edward
authors.initials: E
authors.lastname: Dominguez
authors.forename: Kenneth
authors.initials: K
authors.lastname: Washburn
authors.forename: Emily
authors.initials: E
authors.lastname: Blumberg
authors.forename: Barbara
authors.initials: B
authors.lastname: Alexander
authors.forename: Richard
authors.initials: R
authors.lastname: Freeman
authors.forename: Nigel
authors.initials: N
authors.lastname: Heaton
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003586:Cytomegalovirus Infections / Q000517:prevention & control*; D005260:Female; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016377:Organ Transplantation / Q000009:adverse effects*; D011355:Prodrugs / Q000493:pharmacokinetics*; D000077562:Valganciclovir
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D000077562:Valganciclovir; D015774:Ganciclovir