Michael J. Hanley

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.

The Effect of a High-Fat Meal on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor, in Patients With Advanced Solid Tumors or Lymphoma.

Ixazomib is the first oral proteasome inhibitor to be investigated in the clinic. This clinical study assessed whether the pharmacokinetics of ixazomib would be altered if administered after a high‐calorie, high‐fat meal. In a 2‐period, 2‐sequence, crossover study design, adult patients with advanced solid tumors or lymphoma received a 4‐mg oral dose of ixazomib as immediate‐release capsules on day 1 without food (fasted, administered following an overnight fast) or with food (fed, following consumption of a high‐calorie, high‐fat meal), followed by another dose on day 15 in the alternate food intake condition (fasted to fed or fed to fasted). Twenty‐four patients were enrolled; of these, 15 were included in the pharmacokinetic‐evaluable population. Administration of ixazomib after a high‐fat meal reduced both the rate and extent of absorption of ixazomib. Under fed conditions, the median time to peak plasma concentration (Tmax) of ixazomib was delayed by approximately 3 hours compared with administration in the fasted state (1.02 hours vs 4.0 hours), and there was a 28% reduction in total systemic exposure (area under the curve, AUC) and a 69% reduction in peak plasma concentration (Cmax). Together, the results support the administration of ixazomib on an empty stomach, at least 1 hour before or at least 2 hours after food. These recommendations are reflected in the United States Prescribing Information for ixazomib (clinicaltrials.gov identifier NCT01454076).

Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment

Aim The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. Methods Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single‐dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28‐day cycles. Results Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics‐evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95–1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose‐normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug‐related adverse event; there were no drug‐related grade 4 adverse events. Conclusions In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment.

Effects of Strong CYP3A Inhibition and Induction on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor: Results of Drug‐Drug Interaction Studies in Patients With Advanced Solid Tumors or Lymphoma and a Physiologically Based Pharmacokinetic Analysis

At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib. Eighty‐eight patients were enrolled across the 3 drug‐drug interaction studies; the ixazomib toxicity profile was consistent with previous studies. Ketoconazole and clarithromycin had no clinically meaningful effects on the pharmacokinetics of ixazomib. The geometric least‐squares mean area under the plasma concentration‐time curve from 0 to 264 hours postdose ratio (90%CI) with vs without ketoconazole coadministration was 1.09 (0.91‐1.31) and was 1.11 (0.86‐1.43) with vs without clarithromycin coadministration. Reduced plasma exposures of ixazomib were observed following coadministration with rifampin. Ixazomib area under the plasma concentration‐time curve from time 0 to the time of the last quantifiable concentration was reduced by 74% (geometric least‐squares mean ratio of 0.26 [90%CI 0.18‐0.37]), and maximum observed plasma concentration was reduced by 54% (geometric least‐squares mean ratio of 0.46 [90%CI 0.29‐0.73]) in the presence of rifampin. The clinical drug‐drug interaction study results were reconciled well by a physiologically based pharmacokinetic model that incorporated a minor contribution of CYP3A to overall ixazomib clearance and quantitatively considered the strength of induction of CYP3A and intestinal P‐glycoprotein by rifampin. On the basis of these study results, the ixazomib prescribing information recommends that patients should avoid concomitant administration of strong CYP3A inducers with ixazomib.

Population Pharmacokinetic Analysis of Bortezomib in Pediatric Leukemia Patients: Model‐Based Support for Body Surface Area‐Based Dosing Over the 2‐ to 16‐Year Age Range

This population analysis described the pharmacokinetics of bortezomib after twice‐weekly, repeat‐dose, intravenous administration in pediatric patients participating in 2 clinical trials: the phase 2 AALL07P1 (NCT00873093) trial in relapsed acute lymphoblastic leukemia and the phase 3 AAML1031 (NCT01371981) trial in de novo acute myelogenous leukemia. The sources of variability in the pharmacokinetic parameters were characterized and quantified to support dosing recommendations. Patients received intravenous bortezomib 1.3 mg/m2 twice‐weekly, on days 1, 4, and 8 during specific blocks or cycles of both trials and on day 11 of block 1 of study AALL07P1, in combination with multiagent chemotherapy. Blood samples were obtained and the plasma was harvested on day 8 over 0‐72 hours postdose to measure bortezomib concentrations by liquid chromatography‐tandem mass spectrometry. Concentration‐time data were analyzed by nonlinear mixed‐effects modeling. Covariates were examined using forward addition (P < .01)/backward elimination (P < .001). Data were included from 104 patients (49%/51% acute lymphoblastic leukemia/acute myelogenous leukemia; 60%/40% aged 2‐11 years/12‐16 years). Bortezomib pharmacokinetics were described by a 3‐compartment model with linear elimination. Body surface area adequately accounted for variability in clearance (exponent 0.97), supporting body surface area‐based dosing. Stratified visual predictive check simulations verified that neither age group nor patient population represented sources of meaningful pharmacokinetic heterogeneity not accounted for by the final population pharmacokinetic model. Following administration of 1.3 mg/m2 intravenous bortezomib doses, body surface area–normalized clearance in pediatric patients was similar to that observed in adult patients, thereby indicating that this dose achieves similar systemic exposures in pediatric patients.

A Phase 1 Study to Assess the Relative Bioavailability of Two Capsule Formulations of Ixazomib, an Oral Proteasome Inhibitor, in Patients With Advanced Solid Tumors or Lymphoma

The oral proteasome inhibitor ixazomib is approved in multiple countries in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. Two oral capsule formulations of ixazomib have been used during clinical development. This randomized, 2‐period, 2‐sequence crossover study (Clinicaltrials.gov identifier NCT01454076) assessed the relative bioavailability of capsule B in reference to capsule A in adult patients with advanced solid tumors or lymphoma. The study was conducted in 2 parts. In cycle 1 (pharmacokinetic cycle), patients received a 4‐mg dose of ixazomib as capsule A or capsule B on day 1, followed by a 4‐mg dose of the alternate capsule formulation on day 15. Pharmacokinetic samples were collected over 216 hours postdose. After the pharmacokinetic cycle, patients could continue in the study and receive ixazomib (capsule B only) on days 1, 8, and 15 of each 28‐day cycle. Twenty patients were enrolled; of these, 14 were included in the pharmacokinetic‐evaluable population. Systemic exposures of ixazomib were similar after administration of capsule A or capsule B. The geometric least‐squares mean ratios (capsule B versus capsule A) were 1.16 for Cmax (90% confidence interval [CI], 0.84–1.61) and 1.04 for AUC0–216 (90%CI, 0.91–1.18). The most frequently reported grade 3 drug‐related adverse events were fatigue (15%) and nausea (10%); there were no grade 4 drug‐related adverse events. These results support the combined analysis of data from studies that used either formulation of ixazomib during development.

Model‐Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor

Model‐informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)‐based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib‐based combinations, phase III dose for maintenance treatment), regulatory review (model‐informed QT analysis, benefit–risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient‐centric therapeutic optimization during the development of ixazomib.

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.