title: Effects of hepatic or renal impairment on the pharmacokinetics of aripiprazole.
abstract: OBJECTIVE
  Two studies were conducted to investigate whether the pharmacokinetics of the atypical antipsychotic aripiprazole were altered in individuals with hepatic or renal impairment compared with those with normal hepatic or renal function.
  
  
  METHODS
  Two open-label, single-dose studies.
  
  
  METHODS
  Clinical research unit.
  
  
  METHODS
  Study 1: Subjects with normal hepatic function (n = 6) and subjects with hepatic impairment (Child-Pugh class A [mild, n = 8], B [moderate, n = 8] or C [severe, n = 3]). Study 2: Subjects with normal renal function (creatinine clearance >80 mL/min; n = 7) and subjects with severe renal impairment (creatinine clearance <30 mL/min; n = 6).
  
  
  METHODS
  Single oral dose of aripiprazole 15 mg. PHARMACOKINETIC ANALYSES: Noncompartmental pharmacokinetic analysis was performed using plasma aripiprazole and dehydro-aripiprazole concentration-time data.
  
  
  METHODS
  Study 1 (hepatic impairment study): apparent oral clearance of unbound drug (CL/Fu) and the maximum plasma concentration (Cmax) of aripiprazole; Study 2 (renal impairment study): CL/Fu, Cmax and renal clearance (CL(R)). Safety assessments included 12-lead ECGs, vital sign monitoring, clinical laboratory measurements and assessment of adverse events.f
  
  
  RESULTS
  In the hepatic impairment study, the mean total Cmax of aripiprazole was significantly lower in subjects with severe hepatic impairment compared with those with normal hepatic function (p = 0.04). The fraction of aripiprazole unbound (fu) was significantly greater for subjects with mild (p = 0.02) or severe hepatic impairment (p < 0.01) but not for those with moderate hepatic impairment (p = 0.09) compared with healthy controls. There were no meaningful differences in either the Cmax of unbound aripiprazole or CL/Fu between groups. The mean CL(R) of aripiprazole was negligible (0.04 mL/h/kg in controls and 0.19 mL/h/kg in patients with severe hepatic impairment). In the renal impairment study, the mean total Cmax values were numerically higher (approximately 40%) and the area under the plasma aripiprazole concentration-time curve from time zero to infinity was lower (approximately 19%) in renally impaired subjects versus those with normal renal function; the fu was comparable between groups. Aripiprazole CL(R) was approximately 3-fold higher in renally impaired subjects, but this difference was not statistically significant. No deaths or serious adverse events were reported during either study.
  
  
  CONCLUSIONS
  A single aripiprazole 15-mg dose was well tolerated. There were no meaningful differences in aripiprazole pharmacokinetics between groups of subjects with normal hepatic or renal function and those with either hepatic or renal impairment. Adjustment of the aripiprazole dose does not appear to be required in populations with hepatic or renal impairment.
authors.affiliation: Clinical Pharmacology, Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland 20850, USA. Suresh.Mallikaarjun@otsuka.com
authors.forename: Suresh
authors.initials: S
authors.lastname: Mallikaarjun
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.forename: David W
authors.initials: DW
authors.lastname: Boulton
authors.forename: Steven L
authors.initials: SL
authors.lastname: Bramer
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000068180:Aripiprazole; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011485:Protein Binding; D015363:Quinolones / Q000009:adverse effects / Q000493:pharmacokinetics*; D012720:Severity of Illness Index
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole