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.