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

Autor: Sahasrabudhe SA; Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA., Kartha RV; Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA., Ng M; Department of Hematology and Oncology, Perth Children's Hospital, Nedlands, WA, Australia.; Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA., Basso LM; Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA., Mishra U; Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA., Cloyd JC; Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA., Orchard PJ; Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA., Brundage RC; Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA., Coles LD; Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2021 Dec; Vol. 61 (12), pp. 1638-1645. Date of Electronic Publication: 2021 Aug 27.
DOI: 10.1002/jcph.1943
Abstrakt: 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.
(© 2021, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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