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

Abstract

AIMSOprozomib 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. METHODSTo 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. RESULTSThe 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. CONCLUSIONSThese 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. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2019) 85 530-539 530• Oprozomib, an oral, second-generation, irreversible proteasome inhibitor, has demonstrated anti-tumour activity in preclinical models and clinical trials of patients with haematologic malignancies. • Oprozomib has a half-life of~1 h; cytochrome P450 (CYP) enzymes play a minor role in its metabolism.• An in vitro study showed oprozomib causes time-dependent inhibition of CYP3A4/5 in human liver microsomes. WHAT THIS STUDY ADDS• Oprozomib suppresses CYP3A4 mRNA expression and enzymatic activity in human hepatocytes.• A physiologically-based pharmacokinetic (PBPK) model predicted low potential for oprozomib to inhibit CYP3A4 substrate metabolism in humans, confirmed by the clinical drug-drug interaction study. • This study demonstrates the utility of PBPK modelling in drug interaction risk assessment and clinical programme development.PBPK prediction of oprozomib DDI Br J Clin Pharmacol (2019) 85 530-539 531

An Open-Label Phase 1 Study to Determine the Effect of Lenvatinib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Patients with Advanced Solid Tumors

“…No clinically significant effects of carfilzomib were seen on the pharmacokinetics of midazolam [31]. Oprozomib is a small molecule in development for multiple hematological malignancies and has shown activity as a potential CYP3A4 suppressor [32]. When studied in 18 patients with solid tumors, clinically relevant inhibition was not seen.…”

“…When studied in 18 patients with solid tumors, clinically relevant inhibition was not seen. Uniquely, this study utilized a design in which there was a washout period when patients received neither midazolam nor the study drug [32].…”

Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions

“…Ixazomib and delanzomib have a long terminal plasma half-life of 3.6-11.3 days and 62.0 ± 43.5 h, respectively [54,62]. Though oprozomib has a short plasma half-life of about 1 h resulting from rapid systemic clearance, the recovery of proteasome activity in tissues needed a longer time of 24~72 h due to irreversible binding [63,64]. Therefore, the inductive effects of ixazomib, oprozomib, and delanzomib on drug elimination and DDIs potentially exist, though they are administered once or twice weekly.…”

Physiologically‐based pharmacokinetic model for alectinib, ruxolitinib, and panobinostat in the presence of cancer, renal impairment, and hepatic impairment

“…Moreover, a significant number of cancer patients have HIP (Cabibbo, 2012) and RIP (Launay‐Vacher, 2007). Body physiology and drug pharmacokinetics (PK) can be modified by cancer (Bruera, 1987; Coutant, 2015; Dixon, 2003; Ou, 2019; Schwenger, 2018), RIP (Korashy, 2004; T.D. Nolin, 2003; Pichette, 2003; Rowland Yeo, 2011; Taburet, 1996; Y. Zhang, 2009), and HIP (Johnson, 2010).…”

“…In cancer, there is a prolongation of gastric emptying time (GET) (Bruera, 1987), a decrease in the hepatic expression levels of CYP3A4 and CYP2C9 (Coutant, 2015; Ou, 2019; Schwenger, 2018), and a decrease in plasma albumin and blood hematocrit (Dixon, 2003).…”