title: Pharmacokinetics of topiramate in patients with renal impairment, end-stage renal disease undergoing hemodialysis, or hepatic impairment.
abstract: OBJECTIVE
  Topiramate is primarily renally excreted. Chronic renal and hepatic impairment can affect the clearance of topiramate. Therefore, the objective was to establish dosage guidelines for topiramate in chronic renal impairment, end-stage renal disease (ESRD) undergoing hemodialysis, or chronic hepatic impairment patients.
  
  
  METHODS
  In 3 separate open-label, parallel group studies (n=5-7/group), in patients with mild-moderate and severe renal impairment (based on creatinine clearance), ESRD requiring hemodialysis, or moderate-severe hepatic impairment (based on Child-Pugh classification) and matching healthy participants, pharmacokinetics of a single oral 100mg topiramate was determined.
  
  
  RESULTS
  Compared with healthy controls, overall exposure (AUC0-∞) for topiramate was higher in mild-moderate (85%) and severe renal impairment (117%), consistent with significantly (p<0.05) lower apparent total body clearance (CL/F) and renal clearance (CLR), leading to longer elimination half-life. Both CLR and CL/F of topiramate correlated well with renal function. CL/F was comparable in ESRD and severe renal impairment. Half of usual starting and maintenance dose is recommended in moderate-severe renal impairment patients, and those with ESRD. Hemodialysis effectively removed plasma topiramate with mean dialysis clearance approximately 12-fold greater than CL/F (123.5 mL/min versus 10.8 mL/min). Compared with healthy matched, patients with moderate-severe hepatic impairment exhibited small increase (29%) in topiramate peak plasma concentrations and AUC0-∞ values, consistent with lower CL/F (26%). Topiramate was generally well tolerated.
  
  
  CONCLUSIONS
  Half of usual dose is recommended for moderate-severe renal impairment and ESRD. Supplemental dose may be required during hemodialysis. Dose adjustments might not be required in moderate-severe hepatic impairments; however, the small sample size limits generalization.
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA. Electronic address: PManitpi@its.jnj.com.
authors.forename: Prasarn
authors.initials: P
authors.lastname: Manitpisitkul
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA. Electronic address: CCURTIN@its.jnj.com.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Curtin
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA. Electronic address: KShalayd@its.jnj.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shalayda
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA. Electronic address: SWang7@its.jnj.com.
authors.forename: Shean-Sheng
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA. Electronic address: LFord1@its.jnj.com.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ford
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA. Electronic address: DHeald@its.jnj.com.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Heald
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003401:Creatine / Q000097:blood; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000175:diagnosis / Q000628:therapy; D008107:Liver Diseases / Q000097:blood* / Q000175:diagnosis / Q000628:therapy; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D012720:Severity of Illness Index; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D003401:Creatine
keywords: End-stage renal disease; Epilepsy; Hepatic impairment; Renal impairment; Topiramate