Abstract 13680: Impact of Estimated Glomerular Filtration Rate and Proteinuria on Contrast-induced Nephropathy in Patients With Cardiac Catheterization

Background: Contrast induced nephropathy (CIN) has been a subject of concern to cardiologists in recent year because CIN is associated with increased morbidity, mortality, and healthcare expense. Incidence and risks of contrast induced nephropathy (CIN) after cardiac catheterization are not clear in Japan. Objective: The aim of this study is to investigate the pre-procedural predictors of CIN. Methods: This study, named the study for CIN after cardiac catheterization in Japan (the CINC-J study), is a multicenter cohort study, which examined 1021 patients undergoing cardiac catheterization from 29 hospitals in all over Japan. We divided into 4 groups on the basis of estimated glomerular filtration rate (eGFR: >60 ml•min-1•1.73m-2 = Normal, 45 to 60 = Mild, 30 to 45 = Moderate, <30 = Severe). CIN was defined as an increase in serum creatinine level of 0.5mg/dl or 25% from 48 to 72 hours after contrast-medium injection. Results: The incidence of CIN was significantly higher in patients with proteinuria than those without proteinuria (13.6% vs. 2.8%, p<0.001). In patients without proteinuria, the incidence of CIN was not increased with reducing eGFR, however, in patients with proteinuria, the incidence of CIN was significantly increased with reducing eGFR as shown in the figure. Multivariate-logistic-regression analysis revealed that proteinuria (hazard ratio=3.77; 95% CI: 1.54 to 9.10), contrast volume/eGFR (hazard ratio=1.29; 95% CI: 1.01 to 1.62), Ca antagonist (hazard ratio=3.46; 95% CI: 1.36 to 9.94) were independent predictors of CIN. Conclusions: Proteinuria is the strongest predictor for CIN after cardiac catheterization.

Phase I, safety, pharmacokinetic and biomarker study of BAY 57–9352, an oral VEGFR-2 inhibitor, in a continuous schedule in patients with advanced solid tumors

3040 Background: BAY 57–9352 is a potent competitive inhibitor of the VEGFR-2 (IC50: 6 nM), VEGFR-3 (IC50: 4 nM), PDGFR-β and c-KIT tyrosine kinases. BAY 57–9352 showed tumor efficacy in colon, breast, pancreatic and NSCLC models. Methods: Patients with advanced solid tumors received oral BAY 57–9352 on a continuous basis, in escalating doses. One cycle was defined as 21 days of treatment. Extensive PK and PD (dynamic contrast-enhanced MRI [DCE-MRI]) evaluations were performed. Plasma biomarkers (e.g. VEGF)were also evaluated. Results: Forty patients (median 54 yrs) were enrolled at seven dose levels from 20 mg solution once daily to1500 mg twice daily (bid; 150 mg tablets) for a total of 169 cycles (range 1–17). The most frequent drug-related adverse events were nausea, hypertension, headache, vomiting, hoarseness, rash, dry skin and anorexia. One patient treated at 600 mg bid had a dose-limiting toxicity defined by an increase from grade 2 to 3 hypertension, despite the addition of an ACE-inhibitor and Ca-antagonist on day 8 of cycle 2. Another patient at that same dose level and also on day 8 cycle 2, had grade 3 AST/ALT increase, however this was not assessed as dose-limiting. Both patients continued treatment after dose reductions. Treatment was well tolerated, even at the highest dose levels. One patient with a hemangio-endothelioma (600 mg bid) had a clinical response and one desmoid tumor patient (900 mg bid) had a 53% reduction in tumor volume. BAY 57–9352 AUC increased dose proportionally up to 900 mg bid. The target AUC, based on animal models (5 mg × h/L) was reached in all patients at 900 mg bid. Dose levels exceeding 900 mg bid had similar plasma VEGF biomarker levels. Conclusions: BAY 57–9352 was well tolerated in doses up to 1500 mg bid. Based on safety, PK, PD and biomarker assessments, the recommended dose level is 900 mg bid. A 300 mg tablet is being tested for patient convenience. Combination chemotherapy studies have been started. [Table: see text]