Pharmacoepidemiologic investigation of clonazepam relative clearance by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients

Eiji Yukawa, Masayasu Satou, Toshiharu Nonaka, Miho Yukawa, Shigehiro Ohdo, Shun Higuchi, Takeshi Kuroda, Yoshinobu Goto

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The effects of drug-drug interactions on clonazepam clearance were examined through a retrospective analysis of serum concentration data from pediatric and adult epileptic patients. Patients received clonazepam as monotherapy or in combination with other antiepileptic drugs. A total of 259 serum clonazepam concentrations gathered from 137 patients were used in a population analysis of drug-drug interactions on clonazepam clearance. Data were analyzed using a non-linear mixed-effects modeling (NONMEM) technique. The final model describing clonazepam clearance was CL = 152 • TBW-0.181 • DIF, where CL is clearance (ml/kg/h), TBW is total body weight (kg), and DIF (drug interaction factor) is a scaling factor for concomitant medication with a value of 1 for patients on clonazepam monotherapy, 1.18 for those patients receiving concomitant administration of clonazepam and one antiepileptic drug (carbamazepine or valproic acid), and 2.12 • TBW-0.119 for those patients receiving concomitant administration of clonazepam and more than two antiepileptic drugs. Clonazepam clearance decreased in a weight-related fashion in children, with minimal changes observed in adults. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance. Concomitant administration of clonazepam and valproic acid resulted in a 12% increase in clonazepam clearance. Concomitant administration of clonazepam with two or more antiepileptic drugs resulted in a 23% to 75% increase in clonazepam clearance.

Original languageEnglish
Pages (from-to)81-88
Number of pages8
JournalJournal of Clinical Pharmacology
Volume42
Issue number1
DOIs
Publication statusPublished - 2002

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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