title: Can Perhexiline Be Utilized Without Long-Term Toxicity? A Clinical Practice Audit.
abstract: BACKGROUND
  Perhexiline, originally used as a first-line prophylactic antianginal agent, is now regarded primarily as a treatment for otherwise refractory myocardial ischemia. Recent studies have also demonstrated its short-term utility in heart failure, hypertrophic cardiomyopathy, and inoperable aortic stenosis. Its benefits on myocardial energetics state are potentially counter-balanced by risk of hepatotoxicity and peripheral neuropathy during long-term treatment if drug accumulation occurs. Since perhexiline exhibits complex pharmacokinetics with wide inter-individual variability, its long-term use requires regular plasma concentration monitoring. In this study, the risk of neuro- and hepato-toxicity during long-term perhexiline therapy in relation to the intensity of therapeutic drug monitoring was investigated. Furthermore, determinants of mortality during perhexiline treatment were evaluated.
  
  
  METHODS
  In 170 patients treated with perhexiline for a median of 50 months (interquartile range: 31-94 months), outcomes and relationship to plasma drug concentrations were documented.
  
  
  RESULTS
  Rationale for treatment with perhexiline included myocardial ischemia in 88% and severe systolic heart failure in 38%. Plasma concentrations were within the therapeutic range of 150-600 ng/mL on 65% of assay occasions and toxic levels accounted for 8.8% of measurements. No patient developed hepatotoxicity attributable to perhexiline while 3 developed peripheral neuropathy possibly induced by treatment. Actuarial 5-year survival rate was 83% overall, and 76.3% in patients with associated systolic heart failure.
  
  
  CONCLUSIONS
  This first audit of a large population treated long-term perhexiline demonstrates the following: (1) Although the frequency of monitoring is less than ideal, therapeutic drug monitoring effectively limits occurrence of toxic drug concentrations and virtually eliminates long-term hepato- and neuro-toxicity and (2) Mortality rates during long-term therapy, notably for patients with concomitant heart failure, are surprisingly low.
authors: *Pharmacy Department; and †Cardiology and Clinical Pharmacology Departments, The Queen Elizabeth Hospital, University of Adelaide, South Australia.
authors: Helen
authors: H
authors: Phuong
authors: Bo Y
authors: BY
authors: Choi
authors: Cher-Rin
authors: CR
authors: Chong
authors: Betty
authors: B
authors: Raman
authors: John D
authors: JD
authors: Horowitz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D054143:Heart Failure, Systolic / Q000188:drug therapy / Q000401:mortality; D006801:Humans; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000401:mortality; D010480:Perhexiline / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015996:Survival Rate; D013997:Time Factors
chemical_list: D002317:Cardiovascular Agents; D010480:Perhexiline