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Ganciclovir pharmacokinetics and cytokine dynamics in renal transplant recipients with cytomegalovirus infection
Author(s) -
Tornatore Kathleen M,
Garey Kevin W,
Saigal Navid,
Reed Kris,
Murray Brian,
Ingalls Elizabeth,
DiFrancesco Robin,
Forrest Alan,
Morse Gene,
Venuto Rocco
Publication year - 2001
Publication title -
clinical transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 76
eISSN - 1399-0012
pISSN - 0902-0063
DOI - 10.1034/j.1399-0012.2001.150501.x
Subject(s) - ganciclovir , pharmacokinetics , medicine , dosing , transplantation , renal function , betaherpesvirinae , human cytomegalovirus , pharmacology , cytomegalovirus , therapeutic drug monitoring , cytokine , kidney transplantation , gastroenterology , immunology , herpesviridae , virus , viral disease
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 (Cl Cr ) 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)‐1β, IL‐2, IL‐3, IL‐4, IL‐6, IL‐8, IL‐10, TNF‐α, GM‐CSF, and interferon (IFN)‐γ 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 Cl Cr , suggesting tubular secretion. Peak concentrations for i.v. ganciclovir averaged 8.39±1.87 μg/mL with minimum concentrations of 0.48±0.35 μg/mL. Plasma concentrations were lower but more sustained during a p.o. dosing interval (max=2.12±0.58 μg/mL, min=1.15±0.34 μg/mL). IL‐6, IL‐8, IL‐10, and TNF‐α 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‐α 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‐α, IL‐8, and IFN‐γ 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.