A model-based approach to assess the exposure-response relationship of Lorenzo's oil in adrenoleukodystrophy

Br J Clin Pharmacol. 2016 Jun;81(6):1058-66. doi: 10.1111/bcp.12897. Epub 2016 Apr 3.


Aims: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long chain fatty acids including oleic and erucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. The aims of this study were to characterize the effect of LO administration on plasma C26:0 concentrations and to determine whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys.

Methods: Non-linear mixed effects modelling was performed on 2384 samples collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2-3 mg kg(-1) with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality.

Results: The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.793). Our time-to-event analyses showed that every mg l(-1) increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively).

Conclusions: LO administration significantly reduces the abnormally high plasma C26:0 concentrations in X-ALD patients. Further studies to evaluate the effect of LO on the likelihood of developing brain MRI abnormality are warranted.

Keywords: erucic acid; inborn errors of metabolism; nonmem; population pharmacodynamics.

Publication types

  • Clinical Trial

MeSH terms

  • Adrenoleukodystrophy / blood
  • Adrenoleukodystrophy / metabolism*
  • Adrenoleukodystrophy / pathology*
  • Brain / pathology*
  • Child
  • Child, Preschool
  • Drug Combinations
  • Erucic Acids / blood*
  • Erucic Acids / pharmacokinetics*
  • Erucic Acids / pharmacology
  • Erucic Acids / therapeutic use*
  • Fatty Acids / blood*
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Models, Biological*
  • Neuroimaging
  • Triolein / pharmacokinetics*
  • Triolein / pharmacology
  • Triolein / therapeutic use*


  • Drug Combinations
  • Erucic Acids
  • Fatty Acids
  • Lorenzo's oil
  • erucic acid
  • Triolein