title: A model-based approach to assess the exposure-response relationship of Lorenzo's oil in adrenoleukodystrophy.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.|Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.|Department of Pharmacy Practice, Helwan University, Cairo, Egypt.
authors.forename: Mariam A
authors.initials: MA
authors.lastname: Ahmed
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.|Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Reena V
authors.initials: RV
authors.lastname: Kartha
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.|Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Brundage
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN.|Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: James
authors.initials: J
authors.lastname: Cloyd
authors.affiliation: Division of Biostatistics, University of Minnesota, Minneapolis, MN.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Basu
authors.affiliation: Division of Biostatistics, University of Minnesota, Minneapolis, MN.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Carlin
authors.affiliation: Division of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Jones
authors.affiliation: Peroxisomal Diseases Laboratory, Kennedy Krieger Institute, Baltimore, MD.
authors.forename: Ann B
authors.initials: AB
authors.lastname: Moser
authors.affiliation: Genetics Laboratories, Kennedy Krieger Institute, Baltimore, MD.
authors.forename: Ali
authors.initials: A
authors.lastname: Fatemi
authors.affiliation: Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Gerald V
authors.initials: GV
authors.lastname: Raymond
mesh_terms: D000326:Adrenoleukodystrophy / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D004883:Erucic Acids / Q000097:blood* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D005227:Fatty Acids / Q000097:blood*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008954:Models, Biological; D059906:Neuroimaging; D014304:Triolein / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D004338:Drug Combinations; D004883:Erucic Acids; D005227:Fatty Acids; C079420:Lorenzo's oil; C049811:erucic acid; D014304:Triolein
keywords: erucic acid; inborn errors of metabolism; nonmem; population pharmacodynamics
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