PHARMACOKINETICS OF ABECARNIL IN PATIENTS WITH RENAL-INSUFFICIENCY

Objective: To characterize the pharmacokinetics of a single 5 mg oral dose of abecarnil in subjects with varying degrees of renal impairment . Methods: Twenty-six subjects were enrolled in this open-label parall el-group study, Ten subjects had normal renal function (NRF; creatinin e clearance [CL(CR)]greater than or equal to 85 ml/min/1.73 m(2)), six subjects had mild to moderate renal insufficiency (MMRI; CL(CR) betwe en 25 and 73 ml/min/1.73 m(2)), and 10 subjects had severe renal insuf ficiency (SRI;CL(CR)less than or equal to 10 ml/min/1.73 m(2)), Abecar nil plasma concentrations were determined by means of HPLC, and plasma protein binding was determined by use of ultracentrifugation. Pharmac okinetic parameters were obtained with use of model-independent and mo del-dependent methods. Results: In subjects with SRI, area under the c oncentration-time curve and maximum plasma concentration were reduced by 36% and 31%, respectively, compared with demographically matched su bjects with NRF, The apparent total body clearance in the NRF, MMRI, a nd SRI groups was 13.0 +/- 6.89, 12.9 +/- 3.64, and 25.0 +/- 13 ml/min /kg, and the apparent volume of distribution was 14.0 +/- 3.78, 12.8 /- 2.4, and 19.4 +/- 5.76 L/kg, respectively (mean a SD), The patients with SRI had a significantly lower protein bound fraction than subjec ts with NRF (0.850 +/- 0.077 versus 0.948 +/- 0.023). Despite an incre ase in the free fraction of abecarnil (f(u)), there was no significant change in the apparent unbound total body clearance and unbound volum e of distribution between the SRI and NRF groups, The anticipated full effect of the increase in f(u) among the patients with SRI was not re alized and suggests that the f(u) in tissue may be increased in patien ts with SRI. Conclusion: Dose adjustment will need to be made on the b asis of titration to the desired clinical response and tolerability in patients with SRI just as in subjects with NRF.