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A model-based approach to assess the exposure-response relationship of Lorenzo's oil in adrenoleukodystrophy.
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.
Afiliación
  • Ahmed MA; Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.
  • Kartha RV; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
  • Brundage RC; Department of Pharmacy Practice, Helwan University, Cairo, Egypt.
  • Cloyd J; Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.
  • Basu C; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
  • Carlin BP; Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.
  • Jones RO; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
  • Moser AB; Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.
  • Fatemi A; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
  • Raymond GV; Division of Biostatistics, University of Minnesota, Minneapolis, MN.
Br J Clin Pharmacol ; 81(6): 1058-66, 2016 06.
Article en En | MEDLINE | ID: mdl-26836218
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Trioleína / Ácidos Erucicos / Adrenoleucodistrofia / Ácidos Grasos / Modelos Biológicos Límite: Child / Child, preschool / Humans / Infant / Male Idioma: En Revista: Br J Clin Pharmacol Año: 2016 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Trioleína / Ácidos Erucicos / Adrenoleucodistrofia / Ácidos Grasos / Modelos Biológicos Límite: Child / Child, preschool / Humans / Infant / Male Idioma: En Revista: Br J Clin Pharmacol Año: 2016 Tipo del documento: Article Pais de publicación: Reino Unido