Your browser doesn't support javascript.
loading
Dealing With Variable Drug Exposure Due to Variable Hepatic Metabolism: A Proof-of-Concept Application of Liquid Biopsy in Renal Impairment.
Rostami-Hodjegan, Amin; Al-Majdoub, Zubida M; von Grabowiecki, Yannick; Yee, Ka Lai; Sahoo, Sudhakar; Breitwieser, Wolfgang; Galetin, Aleksandra; Gibson, Christopher; Achour, Brahim.
Afiliación
  • Rostami-Hodjegan A; Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
  • Al-Majdoub ZM; Certara, Princeton, New Jersey, USA.
  • von Grabowiecki Y; Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
  • Yee KL; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
  • Sahoo S; Merck & Co., Inc., Rahway, New Jersey, USA.
  • Breitwieser W; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
  • Galetin A; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
  • Gibson C; Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
  • Achour B; Merck & Co., Inc., Rahway, New Jersey, USA.
Clin Pharmacol Ther ; 116(3): 814-823, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38738484
ABSTRACT
Precision dosing strategies require accounting for between-patient variability in pharmacokinetics (PK), affecting drug exposure, and in pharmacodynamics (PD), affecting response achieved at the same drug concentration at the site of action. Although liquid biopsy for assessing different levels of molecular drug targets has yet to be established, individual characterization of drug elimination pathways using liquid biopsy has recently been demonstrated. The feasibility of applying this approach in conjunction with modeling tools to guide individual dosing remains unexplored. In this study, we aimed to individualize physiologically-based pharmacokinetic (PBPK) models based on liquid biopsy measurements in plasma from 25 donors with different grades of renal function who were previously administered oral midazolam as part of a microdose cocktail. Virtual twin models were constructed based on demographics, renal function, and hepatic expression of relevant pharmacokinetic pathways projected from liquid biopsy output. Simulated exposure (AUC) to midazolam was in agreement with observed data (AFE = 1.38, AAFE = 1.78). Simulated AUC variability with three dosing approaches indicated higher variability with uniform dosing (14-fold) and stratified dosing (13-fold) compared with individualized dosing informed by liquid biopsy (fivefold). Further, exosome screening revealed mRNA expression of 532 targets relevant to drug metabolism and disposition (169 enzymes and 361 transporters). Data related to these targets can be used to further individualize PBPK models for pathways relevant to PK of other drugs. This study provides additional verification of liquid biopsy-informed PBPK modeling approaches, necessary to advance strategies that seek to achieve precise dosing from the start of treatment.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Midazolam / Prueba de Estudio Conceptual / Hígado / Modelos Biológicos Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Clin Pharmacol Ther Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Midazolam / Prueba de Estudio Conceptual / Hígado / Modelos Biológicos Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Clin Pharmacol Ther Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos