A Semi-Mechanistic Population Pharmacokinetic Model of Noscapine in Healthy Subjects Considering Hepatic First-Pass Extraction and CYP2C9 Genotypes.

Autor: Chen Z; Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany. Zhendong.chen@uk-koeln.de., Taubert M; Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany., Chen C; Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany.; Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, 150030, People's Republic of China., Boland J; Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany., Dong Q; Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany., Bilal M; Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany.; Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany., Dokos C; Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany., Wachall B; InfectoPharm Arzneimittel und Consilium GmbH, Heppenheim, Germany., Wargenau M; M.A.R.C.O. GmbH & Co. KG, Düsseldorf, Germany., Scheidel B; ACC GmbH Analytical Clinical Concepts, Leidersbach, Germany., Wiesen MHJ; Pharmacology at the Laboratory Diagnostics Centre, Therapeutic Drug Monitoring, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Schaeffeler E; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Baden-Württemberg, Germany.; University of Tuebingen, Tuebingen, Germany., Tremmel R; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Baden-Württemberg, Germany.; University of Tuebingen, Tuebingen, Germany., Schwab M; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Baden-Württemberg, Germany.; Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany.; Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Baden-Württemberg, Germany., Fuhr U; Department I of Pharmacology, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany.
Jazyk: angličtina
Zdroj: Drugs in R&D [Drugs R D] 2024 Jun; Vol. 24 (2), pp. 187-199. Date of Electronic Publication: 2024 May 29.
DOI: 10.1007/s40268-024-00466-6
Abstrakt: Introduction: Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability.
Objective: This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability.
Methods: Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately.
Results: Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (< 0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3).
Conclusion: The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at "Deutsches Register Klinischer Studien" under registration no. DRKS00017760.
(© 2024. The Author(s).)
Databáze: MEDLINE
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