Ai-Min Hui

Switching from body surface area‐based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis

AIMS This population pharmacokinetic analysis of the investigational oral proteasome inhibitor ixazomib assessed the feasibility of switching from body surface area (BSA)-based to fixed dosing, and the impact of baseline covariates on ixazomib pharmacokinetics. METHODS Data were pooled from 226 adult patients with multiple myeloma, lymphoma or solid tumours in four phase 1 studies, in which ixazomib dosing (oral/intravenous, once/twice weekly) was based on BSA. Population pharmacokinetic modelling was undertaken using nonmem version 7.2. RESULTS Ixazomib pharmacokinetics were well described by a three compartment model with first order absorption and linear elimination. Ixazomib was absorbed rapidly (Ka 0.5 h(-1)), with dose- and time-independent pharmacokinetics. Estimated absolute bioavailability and clearance were 60% and 2l h(-1), respectively. Although a small effect of BSA (range 1.3-2.6 m(2)) was observed on the peripheral volume of distribution (V4), reducing the corresponding inter-individual variability by 12.9%, there was no relationship between BSA and ixazomib clearance (the parameter that dictates total systemic exposure following fixed dosing). Consistently, based on simulations (n = 1000), median AUCs (including interquartile range) were similar after BSA-based (2.23 mg m(-2)) and fixed (4 mg) oral dosing with no trend in simulated AUC vs. BSA for fixed dosing (P = 0.42). No other covariates, including creatinine clearance (22-213.7 ml min(-1)) and age (23-86 years), influenced ixazomib pharmacokinetics. CONCLUSIONS This analysis supports a switch from BSA-based to fixed dosing, without dose modification for mild/moderate renal impairment or age, in future adult studies of ixazomib, simplifying dosing guidance and clinical development.

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

Renal 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.

Abstract B147: A phase 1 drug-drug interaction study between ixazomib, an oral proteasome inhibitor, and rifampin in patients (pts) with advanced solid tumors

Background Ixazomib is an oral proteasome inhibitor under phase 3 investigation in pts with multiple myeloma and AL amyloidosis. Ixazomib citrate, a prodrug, rapidly hydrolyzes to the active moiety, ixazomib, in plasma. Metabolism appears to be the major route of elimination for ixazomib. This phase 1, open-label, multicenter, parallel-group study (NCT01454076) investigated the effect of rifampin, an established strong CYP3A inducer, on the pharmacokinetics (PK) of ixazomib. Methods Adult pts with advanced solid tumors (Eastern Cooperative Oncology Group Performance Status 0 or 1), for which no effective standard treatment was available, were enrolled. Pts in the ixazomib + rifampin arm received a single 4 mg dose of ixazomib on day 8, plus rifampin 600 mg PO on days 1-14 of a 21-day PK cycle. On day 8, ixazomib and rifampin were administered concomitantly and PK samples were collected over 168 hours post-dose. Pts in the reference arm received a single 4 mg dose of ixazomib on day 1 with PK samples collected over 168 hours post-dose. After completion of the 21-day PK cycle, pts could continue in the study and receive ixazomib on days 1, 8, and 15 of 28-day cycles. Plasma PK parameters were estimated by non-compartmental methods. Geometric mean ratios and 90% confidence intervals (CIs) of PK parameters in the ixazomib + rifampin versus ixazomib alone arms were calculated using an ANOVA model. Treatment-emergent adverse events (TEAEs) were assessed using NCI CTCAE version 4.03. Results Eighteen and 20 pts were enrolled to the ixazomib + rifampin and ixazomib alone arms, respectively. To assess the impact of rifampin on ixazomib PK, data from 16 PK-evaluable pts who received ixazomib + rifampin were compared with data from 14 PK-evaluable pts who received ixazomib alone. Demographics and PK parameters are shown in the Table. At data cut-off (4 August 2014), 15 pts (83%) in the ixazomib + rifampin arm had ≥1 TEAE related to study medication. The most common (≥20%) drug-related TEAEs, regardless of grade, were nausea (39%) and fatigue (28%). Three pts (17%) in the ixazomib + rifampin arm experienced ≥1 grade 3 TEAE. Conclusions The strong CYP3A inducer rifampin produced a 74% decrease in ixazomib total systemic exposure. Systemic treatment with strong CYP3A inducers should be avoided in pts receiving ixazomib. Citation Format: Neeraj Gupta, Michael J. Hanley, Karthik Venkatakrishnan, Alberto Bessudo, Sunil Sharma, Bert O9Neil, Bingxia Wang, Ai-Min Hui, John Nemunaitis. A phase 1 drug-drug interaction study between ixazomib, an oral proteasome inhibitor, and rifampin in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B147.