Ganciclovir pharmacokinetics and cytokine dynamics in renal transplant recipients with cytomegalovirus infection

Ganciclovir is considered to be the first-line treatment for cytomegaloviru s (CMV) in renal transplant recipients. This infection is also associated w ith elevations of specific plasma cytokines post-transplantation. To invest igate daily cytokine response to therapy and ganciclovir pharmacokinetics, 4 transplant recipients (3 males, 1 female) with stable renal allograft fun ction diagnosed with CMV infection were enrolled less than 4 months post-tr ansplant. A creatinine clearance (Cl-Cr) was generated by the Cockroft-Gaul t (C-G) equation (range: 42.3-68.5 mL/min) to determine ganciclovir dosing. Blood samples were collected for ganciclovir and cytokine [including inter leukin (IL)-1 beta, 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.) gancic lovir (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. Tot al clearance of ganciclovir was consistently greater than Cl-Cr, suggesting tubular secretion. Peak concentrations for i.v. ganciclovir averaged 8.39 +/- 1.87 mug/mL with minimum concentrations of 0.48 +/- 0.35 mug/mL. Plasma concentrations were lower but more sustained during a p.o. dosing interval (max = 2.12 +/- 0.58 mug/mL, min = 1.15 +/- 0.34 mug/mL). IL-6, IL-8, IL-1 0, 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 4 0.1 +/- 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 dis position and changes in plasma cytokines in renal transplant recipients dur ing CMV infection may provide insight into variable antiviral responses in renal transplant recipients.