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

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 similar to 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 E-max model. A Weibull model was used to characterize the time-to-developing MRI abnormality. RESULTS The population estimate for the fractionalmaximum 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Accumulation of C26:0 is believed to be the major cause of morbidity and mortality in X-ALD patients. Lorenzo's oil (LO) has been shown to reduce C26:0 plasma concentrations in X-ALD patients. The effect of LO on X-ALD clinical outcome is controversial. WHAT THIS STUDY ADDS This is the first study to quantify the effect size of LO on C26:0 and the variability associated with it using a population pharmacodynamic modelling approach. This study sets the foundation for optimizing LO dosage for future studies.