Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment

RATIONALE AND OBJECTIVES. TO determine the safety and pharmacokinetics of g adobenate dimeglumine in a group of subjects with moderate or severe renal impairment. METHODS. The safety and pharmacokinetic profile of gadobenate dimeglumine, a gadolinium (Gd3+) chelate complex in development as a contrast agent for MRT, were evaluated in a placebo controlled, double-blind, multicenter tria l. Subjects with moderate or severe renal impairment (creatinine clearances of 31 to 60 or 10 to 30 mL/min, respectively) received a 0.2-mmol/kg intra venous bolus of Gd3+ or saline placebo. Blood samples (up to 72 hours) and urine and fecal samples (up to 216 hours) were assayed for total Gd3+ conte nt by inductively coupled plasma atomic emission spectroscopy. Gd3+ blood c oncentration/time data were analyzed nonparametrically and parametrically u sing the software program WinNonlin VI,I, RESULTS. Mean (SD) values for Gd3+ area under the curve, blood clearance, s teady-state volume of distribution, renal clearance, and creatinine clearan ce for the moderate group were 862 (392) mu g.h/mL, 56 (25) mL/min, 21 (5) L, 47 (23) mL/min, and 46 (16) mL/min. Values for the severe group were 134 7 (366) mu g.h/mL, 31 (7) mL/min, 19 (6) L, 22 (7) mL/min, and 21 (8) mL/mi n. No Gd3+-related adverse events occurred. Mean values for Gd3+ recovery i n urine and feces for moderate and severe groups were 74% and 6%, and 69% a nd 8% of the dose, respectively, Linear regression analysis demonstrated a significant relation between the level of renal function and blood clearanc e of Gd3+. CONCLUSIONS. Although mean blood clearance and renal clearance values progr essively declined with increasing degree of renal impairment, based on the safety profile and the fact that the administered dose was double the stand ard dose used for MRT purposes, there appears to be no need for dose reduct ion in this population.