Physiologically-based pharmacokinetic modelling to predict oprozomib CYP3A drug-drug interaction potential in patients with advanced malignancies.

Autor: Ou Y; Amgen Inc., South San Francisco, CA, USA., Xu Y; Amgen Inc., Thousand Oaks, CA, USA., Gore L; University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Harvey RD; Winship Cancer Institute of Emory University, Atlanta, GA, USA., Mita A; Cedars-Sinai Medical Center, Los Angeles, CA, USA., Papadopoulos KP; South Texas Accelerated Research Therapeutics, San Antonio, TX, USA., Wang Z; Amgen Inc., South San Francisco, CA, USA., Cutler RE Jr; Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA., Pinchasik DE; Amgen Inc., South San Francisco, CA, USA., Tsimberidou AM; University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2019 Mar; Vol. 85 (3), pp. 530-539. Date of Electronic Publication: 2018 Dec 25.
DOI: 10.1111/bcp.13817
Abstrakt: Aims: Oprozomib is an oral, second-generation, irreversible proteasome inhibitor currently in clinical development for haematologic malignancies, including multiple myeloma and other malignancies. Oprozomib is a rare example of a small molecule drug that demonstrates cytochrome P450 (CYP) mRNA suppression. This unusual property elicits uncertainty regarding the optimal approach for predicting its drug-drug interaction (DDI) risk. The current study aims to understand DDI potential during early clinical development of oprozomib.
Methods: To support early development of oprozomib (e.g. inclusion/exclusion criteria, combination study design), we used human hepatocyte data and physiologically-based pharmacokinetic (PBPK) modelling to predict its CYP3A4-mediated DDI potential. Subsequently, a clinical DDI study using midazolam as the substrate was conducted in patients with advanced malignancies.
Results: The clinical DDI study enrolled a total of 21 patients, 18 with advanced solid tumours. No patient discontinued oprozomib due to a treatment-related adverse event. The PBPK model prospectively predicted oprozomib 300 mg would not cause a clinically relevant change in exposure to CYP3A4 substrates (≤30%), which was confirmed by the results of this clinical DDI study.
Conclusions: These results indicate oprozomib has a low potential to inhibit the metabolism of CYP3A4 substrates in humans. The study shows that cultured human hepatocytes are a more reliable system for DDI prediction than human liver microsomes for studying this class of compounds. Developing a PBPK model prior to a clinical DDI study has been valuable in supporting clinical development of oprozomib.
(© 2018 The British Pharmacological Society.)
Databáze: MEDLINE
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