A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

Abstract

SummaryRenal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single‐dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end‐stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre‐ and post‐dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.

Acute Pancreatitis Associated with Ixazomib in a Multiple Myeloma Patient

“…In a phase 1/1b safety study of ixazomib administered to patients with severe chronic kidney disease or end-stage renal disease requiring hemodialysis, 1 patient died of acute hypoxemic respiratory failure which was thought to be related to the study drug, although acute respiratory distress syndrome from pneumonia or acute pancreatitis were presented as alternative etiologies [5]. No details of any potential relationship between ixazomib and acute pancreatitis in this patient were given.…”

A phase I study to assess the mass balance, excretion, and pharmacokinetics of [14C]-ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors

“…In contrast, moderate and severe hepatic impairment resulted in 20% higher total systemic exposure of ixazomib, with an associated recommendation to reduce the starting dose to 3 mg in this patient population [10, 16], consistent with the greater contribution of hepatic metabolism (confirmed by this study). Of note, severe renal impairment and end-stage renal disease were associated with a 39% higher total systemic exposure compared with patients with normal renal function [17], resulting in a starting dose recommendation of 3 mg for these patients. Although the specific reasons for these observations are not yet known, they may be related to decreased metabolism of ixazomib in the setting of chronic severe renal impairment or end-stage renal disease, as has been described for other drugs [28, 29].…”

“…Based on a population pharmacokinetic (PK) analysis of data from 755 patients enrolled across 10 clinical trials, including the global phase III TOURMALINE-MM1 study, the absolute oral bioavailability and steady-state volume of distribution of ixazomib were estimated to be 58% and 543 L, respectively, with a systemic clearance of 1.86 L/h and a terminal disposition phase half-life (t 1/2 ) of 9.5 days [15]. Ixazomib is highly bound to plasma proteins (99%), primarily serum albumin [16, 17]. At clinically relevant ixazomib concentrations, in vitro studies indicate that ixazomib is metabolized by multiple cytochrome P450 (CYP) and non-CYP proteins with CYP450 enzymes playing only a minor role.…”

“…In dedicated phase I studies, plasma exposures of ixazomib were increased in patients with severe renal impairment (CrCl <30 mL/min), end-stage renal disease requiring dialysis, moderate hepatic impairment (total bilirubin >1.5–3 x ULN), or severe hepatic impairment (total bilirubin >3 x ULN) as compared with patients with normal organ function [16, 17]. Therefore, reduced doses of ixazomib are recommended in these patient populations [10].…”

Ixazomib in the treatment of relapsed multiple myeloma

“…Для иксазомиба не требуется коррекция дозы препарата у пациентов с умеренной почечной или печеночной недостаточностью [11]. У пациентов с тяжелой и диализ-зависимой почечной недостаточностью разовая доза иксазомиба должна быть снижена с 4 до 3 мг [13].…”