1. Introduction
Iberdomide (CC-220) is an orally available agent which binds to the cereblon E3 ubiquitin ligase complex, resulting in proteasomal degradation of Ikaros and Aiolos, which are key transcriptional regulators in hematopoietic cell differentiation of the immune system, including B cells, T cells, monocytes, and plasmacytoid dendritic cells. Iberdomide is a potent antiproliferative agent in B cell-derived tumors, including multiple myeloma (MM) and lymphoma tumor cell lines1-3. Based on these pharmacological activities, iberdomide is being investigated for the treatment of inflammatory and autoimmune-mediated diseases and hematological malignancies including multiple myeloma 4-7.
The pharmacokinetics (PK) of iberdomide have been characterized in several clinical studies. Reports from single-ascending-dose (SAD) and multiple-ascending dose (MAD) studies conducted in healthy subjects showed that the iberdomide PK exposure (e.g., maximum (peak) plasma concentration (Cmax) and area under the plasma concentration time-curve (AUC)) increased in a dose-proportional manner over the tested dose range (0.1 to 6 mg). Following multiple daily oral doses, iberdomide steady state was attained after approximately 7 days, with an accumulation ratio of 2-fold. The median time of maximum observed concentration (Tmax) was observed between 2.5-4 hours postdose. The half-life of iberdomide was estimated to be approximately 9 to 13 hours after single oral dose. Coadministration with food did not affect the oral bioavailability of iberdomide. The systemic exposure of the R-enantiomer of iberdomide (CC-17195) was <9% of iberdomide in the SAD study across all doses and <8% in the MAD study (1 mg) based on AUC 8. Additionally, Gaudy et al. evaluated the iberdomide drug-drug interaction potential with cytochrome P450 (CYP) 3A4/5 enzymes in a clinical study. Results showed that co-administration with itraconazole (a strong CYP3A inhibitor) increased the AUC for plasma iberdomide by approximately 136%; and co-administration with rifampin (CYP3A inducer) substantially decreased the overall exposure (AUC) and Cmax by approximately 82% and 70%, respectively 9.
Based on results from a radiolabeled human mass balance study (data on file, Bristol Myers Squibb), from which 1 mg 14[C] labelled iberdomide was administered in healthy subjects, intact parent molecule in urine and feces constitute 16% and 11% respectively, indicating the absorbed drug is extensively metabolized and excreted mostly as metabolites, with nearly equal contribution from urinary and fecal elimination route. In systemic circulation, iberdomide was the predominant component in human plasma, with M12 being the most prominent circulating metabolite. Based on exposure (AUC), iberdomide and M12 accounted for approximately 59% and 14% of circulating total radioactivity (TRA) exposure, respectively.
CC-220-MM-001 study (herein as MM-001) is an on-going phase 1b/2a, multicenter, open-label, dose-escalation study to determine the maximum tolerated dose, assess the safety, tolerability, pharmacokinetics and efficacy of CC-220 as monotherapy and in combination with other treatments in subjects with multiple myeloma (MM). Iberdomide in combination with dexamethasone (DEX), in combination with DEX and daratumumab (DARA) or bortezomib (BORT), are being investigated in CC-220-MM-001 as treatment regimens and showed encouraging clinical outcome in subjects with heavily pre-treated relapsed and refractory (RR) MM 6,10.
To support the clinical development of iberdomide in RRMM, a parent-metabolite population pharmacokinetic (popPK) model was developed to: 1) characterize the PK of iberdomide and M12 in subjects with RRMM given both molecules were prominent in systemic circulation and pharmacologically active; and 2) assess the influence of covariates on the PK of iberdomide and M12 to inform the dosing strategy in special populations.