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

Mariam A. Ahmed, Reena V. Kartha, Richard C. Brundage, James Cloyd, Cynthia Basu, Bradley P. Carlin, Richard O. Jones, Ann B. Moser, Ali Fatemi, Gerald V. Raymond

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1058-1066
Number of pages9
JournalBritish Journal of Clinical Pharmacology
Issue number6
StatePublished - Jun 1 2016

Bibliographical note

Publisher Copyright:
© 2016 The British Pharmacological Society.


  • erucic acid
  • inborn errors of metabolism
  • nonmem
  • population pharmacodynamics


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