Population Pharmacokinetic Analysis of N-Acetylcysteine in Pediatric Patients With Inherited Metabolic Disorders Undergoing Hematopoietic Stem Cell Transplant

Siddhee A. Sahasrabudhe, Reena V. Kartha, Michelle Ng, Lisa M. Basso, Usha Mishra, James C. Cloyd, Paul J. Orchard, Richard C. Brundage, Lisa D. Coles

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

N-acetylcysteine (NAC) has been used in patients with cerebral adrenoleukodystrophy as an antioxidant agent in association with hematopoietic stem cell transplant (HSCT). However, an understanding of the pharmacokinetic characteristics of intravenous NAC dosing in these patients is limited. If and how NAC pharmacokinetics change following the transplant is unknown. Toward that end, a total of 260 blood samples obtained from 18 pediatric patients with inherited metabolic disorders who underwent HSCT were included in a population pharmacokinetic analysis using nonlinear mixed-effects modeling. NAC clearance (CL) and volume of distribution (V) were explored on 3 occasions: –7, +7, and +21 days relative to transplant. Additionally, the effect of transplant procedure on NAC disposition was explored by accounting for between-occasion variability. The covariate OCC was modeled as a fixed-effect parameter on CL and/or V1. A 2-compartment model adequately described the pharmacokinetics of total NAC. Weight-based allometric scaling on pharmacokinetic parameters was assumed using standard coefficients. Estimates for CL, central (V1), and peripheral volume (V2), and intercompartment clearance were 14.7 L/h, 23.2 L, 17.1 L, 3.99 L/h, respectively, for a 70-kg person. The data only supported between-subject variability in CL (12%) and V1 (41%). Residual variability was estimated to be 16%. HSCT did not change CL and V1 significantly, and analysis across occasions did not reveal any trends. Pharmacokinetic parameter estimates were in general comparable to those reported previously in different populations. These results suggest that dosing of NAC does not need to be altered following HSCT.

Original languageEnglish (US)
Pages (from-to)1638-1645
Number of pages8
JournalJournal of Clinical Pharmacology
Volume61
Issue number12
Early online dateJul 18 2021
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
Funding that supported this work came from an Academic Health Center Faculty Development Grant: Academic Health Center, University of Minnesota, “Improved Therapeutic Intervention for Late‐Stage Cerebral Adrenoleukodystrophy,” 2010‐2012, Cloyd JC and Orchard P (Co‐PIs), Grant #09.18.

Publisher Copyright:
© 2021, The American College of Clinical Pharmacology

Keywords

  • Hematopoietic stem cell transplant
  • Inherited metabolic disorders
  • N-acetylcysteine
  • Pediatric
  • Population pharmacokinetics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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