Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Abstract

Avadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open‐label, nonrandomized, 2‐period, single‐sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) and maximum observed plasma concentration (Cmax), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin.

Single‐Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC‐122) in Subjects With Mild, Moderate, or Severe Renal Impairment

“…Therefore, PK in terms of total concentrations was analyzed in the current study. CC‐122 PK in healthy subjects from this study is generally similar to those in other studies of healthy subjects with normal function . This study also showed that consistent with renal excretion of unchanged parent CC‐122 being one of the major routes of elimination, renal impairment increases overall plasma exposure to CC‐122, as demonstrated by that in subjects with mild, moderate, and severe renal impairment, the total plasma exposure of CC‐122 increased by ∼20%, ∼50%, and ∼120%, respectively.…”

“…Plasma and urine samples were spiked with stable 13 C-labeled CC-122 as an internal standard (IS). CC-122 and [ 13 C 5 ]-CC-122 (IS) from K 3ethylenediaminetetraacetic acid (EDTA) human plasma were extracted by solid-phase extraction using a Tomtec Quadra 4 SPE system with Waters Oasis µ-Elution HLB plate (30 µm).…”

“…AUC and C max appeared to increase in a dose‐proportional manner over the 3‐ to 15‐mg dose range . When CC‐122 was administered with the CYP1A2 inhibitor fluvoxamine, CC‐122 exposure was 154.81% and 107.59% for AUC and C max , respectively, compared with when CC‐122 was administered alone, and when administered with the CYP3A inhibitor itraconazole, CC‐122 exposure was 100.0% and 93.64% for AUC and C max , respectively, compared with when administered alone . In patients with hematologic malignancies or advanced solid tumors, as assessed from the geometric coefficient of variation percentage, moderate to high interpatient variability was noted for both CC‐122 AUC and C max in plasma.…”

“…In vitro human plasma protein binding of CC‐122 was approximately 38% and was concentration independent (data on file). CC‐122 pharmacokinetics (PK) have been studied and adequately characterized in healthy volunteers and patients with hematologic malignancies or advanced solid tumors . In healthy subjects, CC‐122 was absorbed rapidly, the disposition kinetics of CC‐122 appeared to be monophasic, and the terminal elimination phase generally commenced 2 hours postdose and gave a t 1/2 of 7.57 to 8.90 hours.…”

“…CC-122 pharmacokinetics (PK) have been studied and adequately characterized in healthy volunteers and patients with hematologic malignancies or advanced solid tumors. 4,12,13 In healthy subjects, CC-122 was absorbed rapidly, the disposition kinetics of CC-122 appeared to be monophasic, and the terminal elimination phase generally commenced 2 hours postdose and gave a t 1/2 of 7.57 to 8.90 hours. AUC and C max appeared to increase in a dose-proportional manner over the 3-to 15-mg dose range.…”