title: Ganciclovir pharmacokinetics and cytokine dynamics in renal transplant recipients with cytomegalovirus infection.
abstract: Ganciclovir is considered to be the first-line treatment for cytomegalovirus (CMV) in renal transplant recipients. This infection is also associated with elevations of specific plasma cytokines post-transplantation. To investigate daily cytokine response to therapy and ganciclovir pharmacokinetics, 4 transplant recipients (3 males, 1 female) with stable renal allograft function diagnosed with CMV infection were enrolled less than 4 months post-transplant. A creatinine clearance (ClCr) was generated by the Cockroft-Gault (C-G) equation (range: 42.3-68.5 mL/min) to determine ganciclovir dosing. Blood samples were collected for ganciclovir and cytokine [including interleukin (IL)-1beta, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, TNF-alpha, GM-CSF, and interferon (IFN)-gamma analyses after 7 d of intravenous (i.v.) ganciclovir (dosage range: 165-400 mg daily) therapy and again after 7 d of oral (p.o.) ganciclovir (dosage range: 1000 mg, 2-3 times daily) therapy. Pharmacokinetic ganciclovir was described with a two-compartment model. Total clearance of ganciclovir was consistently greater than ClCr, suggesting tubular secretion. Peak concentrations for i.v. ganciclovir averaged 8.39+/-1.87 microg/mL with minimum concentrations of 0.48+/-0.35 microg/mL. Plasma concentrations were lower but more sustained during a p.o. dosing interval (max=2.12+/-0.58 microg/mL, min=1.15+/-0.34 microg/mL). IL-6, IL-8, IL-10, and TNF-alpha were detectable at multiple times during the study periods while the remainder of the cytokines were only intermittently detectable. Average concentrations (i.v. versus p.o. study period) for TNF-alpha were 40.1+/-17.5 versus 22.1+/-11.2 pg/mL, for IL-8 were 17.1+/-15.6 versus 4.12+/-2.59 pg/mL, and for IL-10 were 7.39+/-5.54 versus 2.64+/-1.06 pg/mL. Concentrations were similar for IL-6 during both studies (9.39+/-5.42 versus 14.7+/-14.8 pg/mL). TNF-alpha, IL-8, and IFN-gamma appeared to correlate with CMV antigenemia. Further investigation of ganciclovir disposition and changes in plasma cytokines in renal transplant recipients during CMV infection may provide insight into variable antiviral responses in renal transplant recipients.
authors.affiliation: Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University of Buffalo, NY, USA. tornator@acsu.buffalo.edu
authors.forename: K M
authors.initials: KM
authors.lastname: Tornatore
authors.forename: K W
authors.initials: KW
authors.lastname: Garey
authors.forename: N
authors.initials: N
authors.lastname: Saigal
authors.forename: K
authors.initials: K
authors.lastname: Reed
authors.forename: B
authors.initials: B
authors.lastname: Murray
authors.forename: E
authors.initials: E
authors.lastname: Ingalls
authors.forename: R
authors.initials: R
authors.lastname: DiFrancesco
authors.forename: A
authors.initials: A
authors.lastname: Forrest
authors.forename: G
authors.initials: G
authors.lastname: Morse
authors.forename: R
authors.initials: R
authors.lastname: Venuto
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001499:Bayes Theorem; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000652:urine; D016207:Cytokines / Q000097:blood*; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D005260:Female; D015774:Ganciclovir / Q000493:pharmacokinetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D016030:Kidney Transplantation; D016014:Linear Models; D008297:Male
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D003404:Creatinine; D015774:Ganciclovir