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Phase I Trial of Rosiglitazone in FSGS: I. Report of the FONT Study Group

Melanie S. Joy^*,, Debbie S. Gipson^*, Mary Dike^*, Leslie Powell^*, Amber Thompson^*, Suzanne Vento, Allison Eddy, Agnes B. Fogo^||, Jeffrey B. Kopp^¶, Daniel Cattran^**, and Howard Trachtman

^* University of North Carolina at Chapel Hill, University of North Carolina Kidney Center and Division of Nephrology and Hypertension, Chapel Hill, North Carolina; University of North Carolina at Chapel Hill, School of Pharmacy, Divisions of Pharmacotherapy and Experimental Therapeutics and Molecular Pharmaceutics, Chapel Hill, North Carolina; Schneider Children's Hospital of North Shore–Long Island Jewish Health System, Division of Nephrology, New Hyde Park, New York; Seattle Children's Hospital, Division of Nephrology, Seattle, Washington; ^|| Vanderbilt University Medical Center, Department of Pathology, Nashville, Tennessee; ^¶ National Institute of Diabetes and Digestive and Kidney Diseases, Kidney Disease Branch, National Institutes of Health, Bethesda, Maryland; and ^** Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada

Correspondence: Dr. Howard Trachtman, Schneider Children's Hospital, Division of Nephrology, 269-01 76th Avenue, New Hyde Park, NY 11040. Phone: 718-470-3423; Fax: 718-470-0887; E-mail: trachtma{at}lij.edu

Background and objectives: Patients with primary focal segmental glomerulosclerosis (FSGS) who are resistant to standard therapy are at high risk for progressive chronic kidney disease. Prevention of renal fibrosis represents a promising strategy to slow or halt kidney function decline. This paper presents the results of a Phase I clinical trial of rosiglitazone, a thiazolidinedione, that exerts antifibrotic effects in animal models of FSGS. The primary goal was assessment of safety, tolerability, and pharmacokinetics (PK) of rosiglitazone.

Design, setting, participants, & measurements; Eleven patients, including eight boys/men and three girls/women, with mean age 15 ± 6 yr and estimated GFR 131 ± 62 ml/min/1.73 m², received rosiglitazone, 3 mg/m²/d for 16 wk. PK was assessed twice, after the initial dose and after attaining steady state, in a General Clinical Research Center.

Results: There were no serious adverse events or cardiovascular complications. Rosiglitazone was well tolerated by all patients, as judged by the Treatment Satisfaction Questionnaire for Medication. The PK studies indicated that the area under the curve was decreased by 40 to 50% and oral clearance of rosiglitazone was increased by 250 to 300% in patients with resistant FSGS compared with healthy controls and patients with nonproteinuric stage 2 chronic kidney disease.

Conclusions: Rosiglitazone therapy was safe and well tolerated. PK assessment of potential novel therapies for resistant FSGS is necessary to define appropriate dosing regimens. There is rationale to evaluate the efficacy of rosiglitazone as an antifibrotic agent for resistant FSGS in Phase II/III clinical trials.