Physiologically‐based pharmacokinetic modelling to predict oprozomib CYP3A drug–drug interaction potential in patients with advanced malignancies
| Autor: | Kyriakos P. Papadopoulos, Zhengping Wang, R. Donald Harvey, Yang Xu, Alain C. Mita, Ying Ou, Dawn E. Pinchasik, Apostolia Maria Tsimberidou, Lia Gore, Richard E. Cutler |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Drug Oncology medicine.medical_specialty Physiologically based pharmacokinetic modelling CYP3A Midazolam media_common.quotation_subject Primary Cell Culture Models Biological 030226 pharmacology & pharmacy Young Adult 03 medical and health sciences 0302 clinical medicine Drug Development Pharmacokinetics Neoplasms Internal medicine medicine Cytochrome P-450 CYP3A Humans Drug Interactions Pharmacology (medical) 030212 general & internal medicine Adverse effect Cells Cultured Multiple myeloma Aged media_common Aged 80 and over Pharmacology CYP3A4 business.industry Original Articles Middle Aged medicine.disease Hepatocytes Microsomes Liver Proteasome inhibitor Cytochrome P-450 CYP3A Inhibitors Female business Oligopeptides Proteasome Inhibitors medicine.drug |
| Zdroj: | British Journal of Clinical Pharmacology. 85:530-539 |
| ISSN: | 1365-2125 0306-5251 |
| DOI: | 10.1111/bcp.13817 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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