Abstract # 2240 Poster # 40:

Scheduled for Thursday, June 21, 2007 05:00 PM-07:00 PM: Session 7 (South Main Hall) Poster Presentation

Evaluation of Pioglitazone Induced Fluid Retention in Primates

K. Kavanagh1, M. Berquist2, K. K. Brown2, L. Zhang1 and J. D. Wagner1
1Wake Forest University School of Medicine, Comparative Medicine Clinical Research Center, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1040, USA, 2GlaxoSmithKline
     Pioglitazone is an oral anti-diabetic agent prescribed to improve insulin sensitivity in type 2 diabetic patients. Pioglitazone and agents of its class have been associated with fluid retention and edema which may exacerbate existing or developing congestive heart failure, often present in these patients. Our aims were to evaluate (1) whether fluid shifts were detectable in normoglycemic monkeys, (2) which fluid compartment had detectable changes and (3) whether changes in fluid retention were dose-dependent. Sixteen adult male cynomolgus macaques (Macaca fascicularis) were studied in a Latin square design such that all animals received 0, 1, 2 and 5mg/kg pioglitazone for 6 weeks with 2 weeks washout between periods. At the end of each period animals were weighed (BW) and underwent DEXA scanning. Fluid volumes were measured by Evan's blue dilution for plasma volume (PV), equilibration of sodium bromide for extracellular fluid volume and deuterated water for total body water. Significant [ANOVA, a=0.05] effects were seen in BW at 5mg/kg and expansion of PV at both the 2 and 5mg/kg doses. Additionally, even in metabolically normal monkeys, pioglitazone significantly reduced average blood glucose at 2 and 5mg/kg and triglyceride concentrations at all dose levels. We conclude that in evaluating both the safety and efficacy of pioglitazone-related drugs, that healthy primates are a good model with PV a suitable biomarker for the evaluation of treatment-related fluid retention.