Perhexiline

Perhexiline is an antianginal drug used for treatment of angina that is not controlled with other drugs.

Indications for measuring +
  • Guide dose-adjustment towards optimal drug exposure in relation to drug efficacy and toxicity
    • Significant inter-individual variability in metabolism due to genetic polymorphisms.
      • 5-10% of Caucasian patients are poor metabolisers and will achieve high plasma concentrations (with risk of toxicity) with standard doses
    • Saturable (non-linear) metabolism (i.e. small changes in dosage produce disproportional changes in plasma concentration)
  • Diagnosis
    • Differentiating disease resistant to drug versus inadequate drug exposure (including uncertain adherence)

How to measure

Assay details

Timing of concentration sample

  • With respect to dose interval
    • Perhexiline concentrations should be measured as trough concentrations i.e. just prior to next dose being due
  • With respect to treatment course
    • At steady state (consider practicalities such as testing on weekdays)
      • The standard half-life of perhexiline is 15 hours, with corresponding time to steady state of 3 days. In poor metabolisers half-life will be particularly prolonged e.g. one month.

How to interpret

Reference ranges

Cis-OH-Perhexiline is the predominant perhexiline metabolite. The utility of the perhexiline/metabolite ratio is to inform interpretation of the perhexiline concentration. There is no association between perhexiline/metabolite ratios and clinical response.

  Perhexiline trough concentration
<0.15 mg/L 0.15-0.6 mg/L >0.6 mg/L

Perhexiline/

metabolite ratio

 

>3 
  • Non-adherence
  • Sample too early in treatment course (not yet at steady state)
  • Poor metaboliser within target
  • Too high a dose, but actually not yet at steady state (expect concentrations to keep rising, potentially to toxic concentrations)
  • Poor metaboliser and hence excessive dose

0.05-3
  • Non-adherence
  • Normal metaboliser and underdosed
  • Sample too early in treatment course (not yet at steady state)
  • Normal metaboliser within target
  • Normal metaboliser and excessive dose
<0.05
  • Non-adherence
  • Ultra-rapid metaboliser and underdosed
  • Sample too early in treatment course (not yet at steady state)
  • Ultra-rapid metaboliser within target
  • Ultra-rapid metaboliser and excessive dose

Factors affecting interpretation

Dose individualisation and adjustment

  • Maintenance dose varies according to individual metaboliser status
    • Usual range 100–250 mg once daily but poor metabolisers may only require only 50 mg weekly whereas ultra-rapid metabolisers (perhexiline/metabolite ratio <0.05) may require up to 500 mg daily.
  • Saturable (non-linear) metabolism (i.e. small changes in dosage produce disproportional changes in plasma concentration).

Contacts for help with interpretation

Medicines Information: phone 03 364 0900 or email medicines.information@cdhb.health.nz

Key Resources

Horowitz, J. D., Sia, S. T. B., Macdonald, P. S., et al. Perhexiline maleate treatment for severe angina pectoris—Correlations with pharmacokinetics. International Journal of Cardiology. 1986; 13(2):219–29.

Jones, T. E., Morris, R. G., & Horowitz, J. D. Concentration‐time profile for perhexiline and hydroxyperhexiline in patients at steady state. British Journal of Clinical Pharmacology. 2004;57(3): 263–9.

Phuong, H., Choi, B. Y., Chong, C.-R., et al. Can Perhexiline Be Utilized Without Long-Term Toxicity? A Clinical Practice Audit. Therapeutic Drug Monitoring. 2016;38(1):73–8.

Sallustio, B. C., Westley, I. S., & Morris, R. G. Pharmacokinetics of the antianginal agent perhexiline: Relationship between metabolic ratio and steady‐state dose. British Journal of Clinical Pharmacology. 2002;54(2):107–14.

Last updated

May 2024