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 parallel-group study. Ten subjects had normal renal function (NRF; creatinine clearance [CLCR] > or = 85 ml/min/1.73 m2), six subjects had mild to moderate renal insufficiency (MMRI; CLCR between 25 and 73 ml/min/1.73 m2), and 10 subjects had severe renal insufficiency (SRI; CLCR < or = 10 ml/min/1.73 m2). Abecarnil plasma concentrations were determined by means of HPLC, and plasma protein binding was determined by use of ultracentrifugation. Pharmacokinetic parameters were obtained with use of model-independent and model-dependent methods.


RESULTS
In subjects with SRI, area under the concentration-time curve and maximum plasma concentration were reduced by 36% and 31%, respectively, compared with demographically matched subjects with NRF. The apparent total body clearance in the NRF, MMRI, and 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 +/- SD). The patients with SRI had a significantly lower protein bound fraction than subjects with NRF (0.850 +/- 0.077 versus 0.948 +/- 0.023). Despite an increase in the free fraction of abecarnil (f(u)), there was no significant change in the apparent unbound total body clearance and unbound volume 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 realized and suggests that the f(u) in tissue may be increased in patients with SRI.


CONCLUSIONS
Dose adjustment will need to be made on the basis of titration to the desired clinical response and tolerability in patients with SRI just as in subjects with NRF.
Karara
A H
AH
Department of Drug Safety, Sandoz Research Institute, East Hanover, NJ 07936-1080, USA.
Frye
R F
RF
Hayes
P E
PE
Weaver
M L
ML
Robinson
W T
WT
Rault
R M
RM
Matzke
G R
GR
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044383:Black People; D001798:Blood Proteins / Q000378:metabolism; D002243:Carbolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D012044:Regression Analysis; D051437:Renal Insufficiency / Q000378:metabolism*; D044465:White People
D014151:Anti-Anxiety Agents; D001798:Blood Proteins; D002243:Carbolines; D003404:Creatinine; C062769:abecarnil