A model‐based approach to assess the exposure–response relationship of Lorenzo's oil in adrenoleukodystrophy. (3rd April 2016)

• Record Type: Journal Article
• Authors: Ahmed, Mariam A.; Kartha, Reena V.; Brundage, Richard C.; Cloyd, James; Basu, Cynthia; Carlin, Bradley P.; Jones, Richard O.; Moser, Ann B.; Fatemi, Ali; Raymond, Gerald V.
• Is Part Of: British journal of clinical pharmacology. Volume 81:Number 6(2016:Jun.)
• Page Start: 1058
• Page End: 1066
• Publication Date: 2016-04-03
• Subjects: erucic acid -- inborn errors of metabolism -- nonmem -- population pharmacodynamics; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12897
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : 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.