Your browser doesn't support javascript.
loading
Exploring the impact of CYP2D6 and UGT2B7 gene-drug interactions, and CYP-mediated DDI on oxycodone and oxymorphone pharmacokinetics using physiologically-based pharmacokinetic modeling and simulation.
Klose, Marian; Cristofoletti, Rodrigo; Silva, Carolina de Miranda; Mangal, Naveen; Turgeon, Jacques; Michaud, Veronique; Lesko, Lawrence J; Schmidt, Stephan.
Afiliación
  • Klose M; Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Florida.
  • Cristofoletti R; Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Florida.
  • Silva CM; Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Florida.
  • Mangal N; Gilead Sciences, Foster City, California, USA.
  • Turgeon J; GalenusRx Inc, Florida, USA.
  • Michaud V; GalenusRx Inc, Florida, USA; Faculty of Pharmacy, Université de Montréal, Canada.
  • Lesko LJ; Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Florida.
  • Schmidt S; Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida, Florida. Electronic address: sschmidt@cop.ufl.edu.
Eur J Pharm Sci ; 194: 106689, 2024 Mar 01.
Article en En | MEDLINE | ID: mdl-38171419
ABSTRACT
Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound. While CYP2D6-mediated gene-drug-interactions (GDIs) and drug-drug interactions (DDIs) are well-studied, they only account for a portion of the variability in oxycodone and oxymorphone exposure. The combined impact of CYP2D6-mediated GDIs and DDIs, CYP3A4-mediated DDIs, and UGT2B7 GDIs is not fully understood yet and hard to study in head-to-head clinical trials given the relatively large number of scenarios. Instead, we propose the use of a physiologically-based pharmacokinetic model that integrates available information on oxycodone's metabolism to characterize and predict the impact of DDIs and GDIs on the exposure of oxycodone and its major, pharmacologically-active metabolite oxymorphone. To this end, we first developed and verified a PBPK model for oxycodone and its metabolites using published clinical data. The verified model was then applied to determine the dose-exposure relationship of oxycodone and oxymorphone stratified by CYP2D6 and UGT2B7 phenotypes respectively, and administered perpetrators of CYP-based drug interactions. Our simulations demonstrate that the combination of CYP2D6 UM and a UGT2B7Y (268) mutation may lead to a 2.3-fold increase in oxymorphone exposure compared to individuals who are phenotyped as CYP2D6 NM / UGT2B7 NM. The extent of oxymorphone exposure increases up to 3.2-fold in individuals concurrently taking CYP3A4 inhibitors, such as ketoconazole. Inhibition of the CYP3A4 pathway results in a relative increase in the partial metabolic clearance of oxycodone to oxymorphone. Oxymorphone is impacted to a higher extent by GDIs and DDIs than oxycodone. We predict oxymorphone exposure to be highest in CYP2D6 UMs/UGT2B7 PMs in the presence of ketoconazole (strong CYP3A4 index inhibitor) and lowest in CYP2D6 PMs/UGT2B7 NMs in the presence of rifampicin (strong CYP3A4 index inducer) covering a 55-fold exposure range.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxicodona / Oximorfona Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Eur J Pharm Sci Asunto de la revista: FARMACIA / FARMACOLOGIA / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxicodona / Oximorfona Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Eur J Pharm Sci Asunto de la revista: FARMACIA / FARMACOLOGIA / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos