Clinical Pharmacokinetics

, Volume 44, Issue 5, pp 495–507 | Cite as

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

  • Hugh Wiltshire
  • Sarapee Hirankarn
  • Colm Farrell
  • Carlos Paya
  • Mark D. Pescovitz
  • Atul Humar
  • Edward Dominguez
  • Kenneth Washburn
  • Emily Blumberg
  • Barbara Alexander
  • Richard Freeman
  • Nigel Heaton
Original Research Article



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.


  1. 1.
    Pereyra F, Rubin RH. Prevention and treatment of cytomegalovirus infection in solid organ transplant recipients. Curr Opin Infect Dis 2004; 17: 357–61PubMedCrossRefGoogle Scholar
  2. 2.
    Sagedal S, Nordal KP, Hartmann A, et al. A prospective study of the natural course of cytomegalovirus infection and disease in renal allograft recipients. Transplantation 2000; 70: 1166–74PubMedCrossRefGoogle Scholar
  3. 3.
    Sancho A, Gorriz JL, Crespo JF, et al. Prophylaxis of cytomegalovirus disease with intravenous ganciclovir in renal transplantation. Transplant Proc 1999; 31: 2337–8PubMedCrossRefGoogle Scholar
  4. 4.
    Wreghitt TG, Abel SJ, McNeil K, et al. Intravenous ganciclovir prophylaxis for cytomegalovirus in heart, heart-lung, and lung transplant recipients. Transpl Int 1999; 12: 254–60PubMedCrossRefGoogle Scholar
  5. 5.
    Gane E, Saliba F, Valdecasas GJ, et al. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver transplant recipients. Lancet 1997; 350: 1729–33PubMedCrossRefGoogle Scholar
  6. 6.
    Paya CV, Wilson JA, Espy MJ, et al. Preemptive use of oral ganciclovir to prevent cytomegalovirus infection in liver transplant patients: a randomized, placebo-controlled trial. J Infect Dis 2002; 185: 854–60PubMedCrossRefGoogle Scholar
  7. 7.
    Hertz MI, Jordan C, Savik SK, et al. Randomized trial of daily versus three-times-weekly prophylactoc ganciclovir after lung and heart-lung transplantation. J Heart Lung Transplant 1998: 17: 913–20PubMedGoogle Scholar
  8. 8.
    Pescovitz MD, Pruett TL, Gonwa T, et al. Oral ganciclovir dosing in transplant recipients and dialysis patients based on renal function. Transplantation 1998; 66: 1104–7PubMedCrossRefGoogle Scholar
  9. 9.
    Pescovitz MD, Rabkin J, Merion RM, et al. Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother 2000; 44: 2811–5PubMedCrossRefGoogle Scholar
  10. 10.
    Jung D, Dorr A. Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J Clin Pharmacol 1999; 39: 800–4PubMedCrossRefGoogle Scholar
  11. 11.
    Czock D, Scholle C, Rasche FM, et al. Pharmacokinetics of valganciclovir and ganciclovir in renal impariment. Clin Pharmacol Ther 2002; 72: 142–50PubMedCrossRefGoogle Scholar
  12. 12.
    Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002; 346: 1119–26PubMedCrossRefGoogle Scholar
  13. 13.
    Brown F, Banken L, Saywell K, et al. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet 1999; 37: 167–76PubMedCrossRefGoogle Scholar
  14. 14.
    Pescovitz MD. Oral ganciclovir and pharmacokinetics of valganciclovir in liver transplant recipients. Transpl Infect Dis 1999; 1: 31–4PubMedGoogle Scholar
  15. 15.
    Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Valganciclovir Solid Organ Transplant Study Group. Am J Transplant 2004; 4: 611–20PubMedCrossRefGoogle Scholar
  16. 16.
    Chu F, Kiang CH, Sung ML, et al. A rapid, sensitive HPLC method for the determination of ganciclovir in human plasma and serum. J Pharm Biomed Anal 1999; 21: 657–67PubMedCrossRefGoogle Scholar
  17. 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
  18. 18.
    Karlsson MO, Jonsson EN, Wiltse CG, et al. Assumption testing in population pharmacokinetic models: illustrated with an analysis of moxonidine data from congestive heart failure patients. J Pharmacokinet Biopharm 1998; 26: 207–46PubMedGoogle Scholar
  19. 19.
    Beal SL, Sheiner LB. NONMEM users guides. San Francisco (CA): NONMEM Project Group, University of California, 1992Google Scholar
  20. 20.
    Winston DJ, Imagawa DK, Holt CD, et al. Long-term ganciclovir prophylaxis eliminates serious cytomegalovirus disease in liver transplant recipients receiving OKT3 therapy for rejection. Transplantation 1995; 60: 1357–60PubMedGoogle Scholar
  21. 21.
    Seu P, Winston DJ, Holt CD, et al. Long-term ganciclovir prophylaxis for successful prevention of primary cytomegalovirus (CMV) disease in CMV-seronegative liver transplant recipients with CMV-seropositive donors. Transplantation 1997; 64: 1614–7PubMedCrossRefGoogle Scholar
  22. 22.
    Flechner SM, Avery RK, Fisher R, et al. A randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Transplantation 1998; 66: 1682–8PubMedCrossRefGoogle Scholar
  23. 23.
    Griffy KG. Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons. AIDS 1996; 10 Suppl. 4: S3–6PubMedGoogle Scholar
  24. 24.
    Ganapathy ME, Huang W, Wang H, et al. Valacyclovir: a substrate for the intestinal and peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun 1998; 19: 470–5CrossRefGoogle Scholar
  25. 25.
    Sinko PJ, Balimane PV. Carrier-mediated intestinal absorption of valacyclovir, the L-valyl ester prodrug of acyclovir: interactions with peptides, organic anions and organic cations in rats. Biopharm Drug Dispos 1998; 19: 209–17PubMedCrossRefGoogle Scholar
  26. 26.
    Lake KD, Fletcher CV, Love KR, et al. Ganciclovir pharmacokinetics during renal impairment. Antimicrob Agents Chemother 1988; 32: 1899–900PubMedCrossRefGoogle Scholar
  27. 27.
    Sommadossi JP, Bevan R, Ling T, et al. Clinical pharmacokinetics of ganciclovir in patients with normal and impaired renal function. Rev Infect Dis 1988; 10 Suppl. 3: S507–14PubMedCrossRefGoogle Scholar
  28. 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
  29. 29.
    Fishman JA, Doran MT, Volpicelli SA, et al. Dosing of intravenous ganciclovir for the prophylaxis and treatment of cytomegalovirus infection in solid organ transplant recipients. Transplantation 2000; 69: 389–94PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Hugh Wiltshire
    • 1
  • Sarapee Hirankarn
    • 2
  • Colm Farrell
    • 2
  • Carlos Paya
    • 3
  • Mark D. Pescovitz
    • 4
  • Atul Humar
    • 5
  • Edward Dominguez
    • 6
  • Kenneth Washburn
    • 7
  • Emily Blumberg
    • 8
  • Barbara Alexander
    • 9
  • Richard Freeman
    • 10
  • Nigel Heaton
    • 11
  1. 1.Roche Products LtdWelwyn Garden CityUK
  2. 2.GloboMax — a division of ICON plcMarlowUK
  3. 3.Mayo ClinicRochesterUSA
  4. 4.Departments of Surgery/Microbiology/ImmunologyIndiana UniversityIndianapolisUSA
  5. 5.Toronto General HospitalTorontoCanada
  6. 6.University of Nebraska Medical CenterOmahaUSA
  7. 7.University of Texas Health Science CenterSan AntonioUSA
  8. 8.Hospital of the University of PennsylvaniaPhiladelphiaUSA
  9. 9.Duke University Medical CenterDurhamUSA
  10. 10.New England Medical CenterBostonUSA
  11. 11.King’s CollegeLondonUK

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