Phase I trial of rosiglitazone in FSGS: I. Report of the FONT Study Group.
OBJECTIVE
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.


METHODS
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 m(2), received rosiglitazone, 3 mg/m(2)/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.
Joy
Melanie S
MS
University of North Carolina at Chapel Hill, University of North Carolina Kidney Center and Division of Nephrology and Hypertension, Chapel Hill, NC, USA.
Gipson
Debbie S
DS
Dike
Mary
M
Powell
Leslie
L
Thompson
Amber
A
Vento
Suzanne
S
Eddy
Allison
A
Fogo
Agnes B
AB
Kopp
Jeffrey B
JB
Cattran
Daniel
D
Trachtman
Howard
H
D000284:Administration, Oral; D000293:Adolescent; D000367:Age Factors; D001830:Body Surface Area; D002170:Canada; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D011507:Proteinuria / Q000188:drug therapy; D000077154:Rosiglitazone; D012709:Serum Albumin / Q000378:metabolism; D013256:Steroids / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
D007166:Immunosuppressive Agents; D012709:Serum Albumin; D013256:Steroids; D045162:Thiazolidinediones; D000077154:Rosiglitazone