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

Abstract

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 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.

Figure 1.

Graphic illustration of the baseline and 16-wk values for each specific laboratory test. Each data point represents an individual patient who participated in the Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FSGS) (FONT) study. The mean ± SD values at baseline and 16 wk, respectively, for each figure are: (a) GFR 131 ± 62 and 117 ± 67 ml/min/1.7m²; (b) urinary protein:creatinine ratio (UP:Cr) 5.5 ± 2.6 and 7.2 ± 4.5, based on the ten patients who completed the 16-wk treatment period; (c) albumin 2.3 ± 1.0 and 2.2 ± 1.1 g/dl); and (d) glucose 84 ± 26 and 76 ± 11 mg/dl.

Figure 2.

A representative single-dose plasma concentration versus time curve for rosiglitazone and N-desmethylrosiglitazone.