title: A hierarchical Bayesian approach for combining pharmacokinetic/pharmacodynamic modeling and Phase IIa trial design in orphan drugs: Treating adrenoleukodystrophy with Lorenzo's oil.
abstract: X-linked adrenoleukodystrophy (X-ALD) is a rare, progressive, and typically fatal neurodegenerative disease. Lorenzo's oil (LO) is one of the few X-ALD treatments available, but little has been done to establish its clinical efficacy or indications for its use. In this article, we analyze data on 116 male asymptomatic pediatric patients who were administered LO. We offer a hierarchical Bayesian statistical approach to understand LO pharmacokinetics (PK) and pharmacodynamics (PD) resulting from an accumulation of very long-chain fatty acids. We experiment with individual- and observational-level errors and various choices of prior distributions and deal with the limitation of having just one observation per administration of the drug, as opposed to the more usual multiple observations per administration. We link LO dose to the plasma erucic acid concentrations by PK modeling, and then link this concentration to a biomarker (C26, a very long-chain fatty acid) by PD modeling. Next, we design a Bayesian Phase IIa study to estimate precisely what improvements in the biomarker can arise from various LO doses while simultaneously modeling a binary toxicity endpoint. Our Bayesian adaptive algorithm emerges as reasonably robust and efficient while still retaining good classical (frequentist) operating characteristics. Future work looks toward using the results of this trial to design a Phase III study linking LO dose to actual improvements in health status, as measured by the appearance of brain lesions observed via magnetic resonance imaging.
authors.affiliation: a Division of Biostatistics , School of Public Health, University of Minnesota , Minneapolis , Minnesota , USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Basu
authors.affiliation: b Experimental and Clinical Pharmacology, College of Pharmacy , University of Minnesota , Minneapolis , Minnesota , USA.|c College of Pharmacy , Helwan University , Helwan , Egypt.
authors.forename: Mariam A
authors.initials: MA
authors.lastname: Ahmed
authors.affiliation: d Center for Orphan Drug Research, College of Pharmacy , University of Minnesota , Minneapolis , Minnesota , USA.
authors.forename: Reena V
authors.initials: RV
authors.lastname: Kartha
authors.affiliation: b Experimental and Clinical Pharmacology, College of Pharmacy , University of Minnesota , Minneapolis , Minnesota , USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Brundage
authors.affiliation: e Department of Neurology , University of Minnesota Medical School , Minneapolis , Minnesota , USA.
authors.forename: Gerald V
authors.initials: GV
authors.lastname: Raymond
authors.affiliation: d Center for Orphan Drug Research, College of Pharmacy , University of Minnesota , Minneapolis , Minnesota , USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
authors.affiliation: a Division of Biostatistics , School of Public Health, University of Minnesota , Minneapolis , Minnesota , USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Carlin
mesh_terms: D000326:Adrenoleukodystrophy / Q000188:drug therapy*; D001499:Bayes Theorem; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004883:Erucic Acids / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009965:Orphan Drug Production; D012107:Research Design; D014304:Triolein / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D004338:Drug Combinations; D004883:Erucic Acids; C079420:Lorenzo's oil; C049811:erucic acid; D014304:Triolein
keywords: Adaptive clinical trial design; Bayesian hierarchical modeling; Lorenzo’s oil; PK/PD modeling; X-ALD; orphan disease; pediatric drug development