A Phase 1 Study to Assess Pharmacokinetics (PK) and Safety of Ixazomib, an Oral Proteasome Inhibitor, in Patients with Moderate or Severe Hepatic Impairment

Background

The investigational oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in patients with multiple myeloma and amyloidosis. Metabolism is the major mechanism of ixazomib clearance; accordingly, hepatic impairment may increase ixazomib exposures. PK and safety data suggested no clinically relevant PK alterations in patients with mild hepatic impairment (Gupta et al BJCP 2015). This study (NCT01912222) was performed to characterize the PK of ixazomib in patients with moderate or severe hepatic impairment, as defined by the NCI Organ Dysfunction Working Group, to develop dosing recommendations for these specific patient populations.

Methods

Eligible adults had advanced malignancies for which no further effective therapy was available. Twelve PK-evaluable patients were planned to be enrolled to each of the normal (N), moderate (M) or severe (S) hepatic impairment groups. Patients received a single dose of ixazomib on day 1; those in the N, M, and S groups received ixazomib 4, 2.3, and 1.5 mg, respectively. Blood samples were collected at multiple time points for 15 days after dosing to characterize single dose PK (18 samples in total, 0.5–8 hr on day 1, days 2–8, days 11, 12, and 15). After completion of PK sampling, patients could continue on the study and receive ixazomib on days 1, 8, and 15 of 28-day cycles. Geometric mean ratios and 90% CIs of unbound dose-normalized (DN) PK parameters in the hepatic impairment vs normal groups were calculated using an ANOVA model. Treatment-emergent adverse events (TEAEs) were assessed using NCI CTCAE version 4.03.

Results 

Forty-eight patients were enrolled (13, 15, and 20 patients to the N, M, and S groups, respectively); 32 were Caucasian, 10 African American, 2 Asian, and 4 other. Mean age was 56 years (range 24–83), mean weight 76 kg (range 43–127), and mean body surface area 1.9 m² (range 1.4–2.5); 28 (58%) were male. The most common cancers were hepatocellular carcinoma (21%) and colorectal carcinoma, with or without liver metastases (10%). All patients in the S group had liver dysfunction due to primary or metastatic tumors. Forty-three patients had reportable PK parameters (C_max or AUC) and were PK-evaluable (12 N, 13 M, 18 S). PK parameters are reported in the Table. Ixazomib was rapidly absorbed in all 3 hepatic function groups examined, with a median T_maxof 0.95–1.5 hours. Ixazomib was highly bound to plasma proteins with a similar mean fraction bound (~99%) in all 3 groups.

Only 1 (2%) patient continued on study for more than 3 cycles (endometrial carcinoma, 10 cycles). Discontinuations were due to progression (75% of discontinuations), TEAEs or death related to progression. The most common TEAEs were nausea (38%), fatigue (31%), peripheral edema (31%), vomiting (27%), dyspnea (23%), decreased appetite (21%), and hyperbilirubinemia (21%). Most patients (77%) had a grade ≥3 TEAE, including 15% with a grade ≥3 study drug-related TEAE (dehydration [6%], fatigue [4%], anemia [2%], and fall [2%]); no patient had a study drug-related grade 4 TEAE.  There were 14 on-study deaths, all of which were considered related to disease progression.

Conclusions 

Unbound systemic exposures of ixazomib were 27% higher in patients with moderate or severe hepatic impairment versus those in patients with normal hepatic function. A reduced starting ixazomib dose of 3 mg is recommended for patients with moderate or severe hepatic impairment.

 

Hepatic function group	PK parameters Geometric mean (%CV)		Hepatic impaired vs Normal Least-squares geometric mean ratio (90% CI)
	Unbound DN Cmax (ng/mL/mg)	Unbound DN AUC (ng.hr/mL/mg)	Unbound DN Cmax	Unbound DN AUC
Normal	0.127 (47)	2.41 (50)	N/A	N/A
Moderate	0.162 (80)	3.19 (61)	1.27 (0.74–2.18)	1.32 (0.70–2.50)
Severe	0.154 (84)	2.96 (63)	1.21 (0.74–2.01)	1.23 (0.66–2.29)
Moderate/Severe (combined)	0.158 (81)	3.07 (61)	1.24 (0.79–1.95)	1.27 (0.75–2.16)

C_max, maximum plasma concentration; CV, coefficient of variation; AUC, area under the plasma concentration-time curve