Ontology highlight
ABSTRACT: 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.
SUBMITTER: Ou Y
PROVIDER: S-EPMC6379218 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
British journal of clinical pharmacology 20181225 3
<h4>Aims</h4>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 e ...[more]