Population Pharmacokinetic Analysis of N-acetylcysteine in Pediatric Patients with Inherited Metabolic Disorders Undergoing Hematopoietic Stem Cell Transplant.

Abstract

N-acetylcysteine (NAC) has been utilized in patients with cerebral adrenoleukodystrophy(cALD) 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 changes following the transplant is unknown. Toward that end, a total of 260 blood samples obtained from 18 pediatric patients with inherited metabolic disorders (IMDs) who underwent HSCT were included in a population pharmacokinetic analysis using non-linear mixed-effects modeling. NAC clearance (CL) and volume of distribution (V) were explored at three occasions (OCC) -7, +7, +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 two-compartment model adequately described the pharmacokinetics of total NAC. Weight-based allometric scaling on pharmacokinetic parameters was assumed using standard coefficients. Estimates for clearance (CL), central (V1) and peripheral volume (V2) and intercompartment clearance (Q) were 14.7 L/h, 23.2 L, 17.1 L, 3.99 L/h, respectively for a 70kg 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. This article is protected by copyright. All rights reserved.