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Antimicrobial Agents and Chemotherapy, July 2009, p. 3017-3023, Vol. 53, No. 7
0066-4804/09/$08.00+0 doi:10.1128/AAC.00836-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Population Pharmacokinetics of Ganciclovir in Solid-Organ Transplant Recipients Receiving Oral Valganciclovir
N. Perrottet,1
C. Csajka,1
M. Pascual,2
O. Manuel,2
F. Lamoth,2
P. Meylan,3
J. D. Aubert,2,4
J. P. Venetz,2
P. Soccal,5
L. A. Decosterd,1
J. Biollaz,1 and
T. Buclin1*
Division of Clinical Pharmacology and Toxicology, University Hospital, Lausanne, Switzerland,1 Transplantation Centre, University Hospital, Lausanne, Switzerland,2 Microbiology Institute, University Hospital, Lausanne, Switzerland,3 Pneumology Service, University Hospital, Lausanne, Switzerland,4 Pneumology Service, University Hospital, Geneva, Switzerland5
Received 24 June 2008/ Returned for modification 22 October 2008/ Accepted 17 March 2009
Valganciclovir (VGC) is an oral prodrug of ganciclovir (GCV) recently introduced for prophylaxis and treatment of cytomegalovirus infection. Optimal concentration exposure for effective and safe VGC therapy would require either reproducible VGC absorption and GCV disposition or dosage adjustment based on therapeutic drug monitoring (TDM). We examined GCV population pharmacokinetics in solid organ transplant recipients receiving oral VGC, including the influence of clinical factors, the magnitude of variability, and its impact on efficacy and tolerability. Nonlinear mixed effect model (NONMEM) analysis was performed on plasma samples from 65 transplant recipients under VGC prophylaxis or treatment. A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by the glomerular filtration rate (GFR), patient gender, and graft type (clearance/GFR = 1.7 in kidney, 0.9 in heart, and 1.2 in lung and liver recipients) with interpatient and interoccasion variabilities of 26 and 12%, respectively. Body weight and sex influenced central volume of distribution (V1 = 0.34 liter/kg in males and 0.27 liter/kg in females [20% interpatient variability]). No significant drug interaction was detected. The good prophylactic efficacy and tolerability of VGC precluded the demonstration of any relationship with GCV concentrations. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of the GCV profile after treatment with oral VGC, routine TDM does not appear to be clinically indicated in solid-organ transplant recipients. However, GCV plasma measurement may still be helpful in specific clinical situations.
* Corresponding author. Mailing address: Division de Pharmacologie clinique, Hôpital de Beaumont 06, Département de Médecine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne CHUV, Switzerland. Phone: 41 21 314 42 60. Fax: 41 21 314 42 66. E-mail: thierry.buclin{at}chuv.ch
Published ahead of print on 23 March 2009.
Antimicrobial Agents and Chemotherapy, July 2009, p. 3017-3023, Vol. 53, No. 7
0066-4804/09/$08.00+0 doi:10.1128/AAC.00836-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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