Larisa Reyderman

Mass Balance Study of [14C]Eribulin in Patients with Advanced Solid Tumors

This mass balance study investigated the metabolism and excretion of eribulin, a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, in patients with advanced solid tumors. A single approximately 2 mg (approximately 80 μCi) dose of [14C]eribulin acetate was administered as a 2 to 5 min bolus injection to six patients on day 1. Blood, urine, and fecal samples were collected at specified time points on days 1 to 8 or until sample radioactivity was ≤1% of the administered dose. Mean plasma eribulin exposure (627 ng · h/ml) was comparable with that of total radioactivity (568 ng Eq · h/ml). Time-matched concentration ratios of eribulin to total radioactivity approached unity in blood and plasma, indicating that unchanged parent compound constituted almost all of the eribulin-derived radioactivity. Only minor metabolites were detected in plasma samples up to 60 min postdose, pooled across patients, each metabolite representing ≤0.6% of eribulin. Elimination half-lives for eribulin (45.6 h) and total radioactivity (42.3 h) were comparable. Eribulin-derived radioactivity excreted in feces was 81.5%, and that of unchanged eribulin was 61.9%. Renal clearance (0.301 l/h) was a minor component of total eribulin clearance (3.93 l/h). Eribulin-derived radioactivity excreted in urine (8.9%) was comparable with that of unchanged eribulin (8.1%), indicating minimal excretion of metabolite(s) in urine. Total recovery of the radioactive dose was 90.4% in urine and feces. Overall, no major metabolites of eribulin were detected in plasma. Eribulin is eliminated primarily unchanged in feces, whereas urine constitutes a minor route of elimination.

Pharmacokinetics of eribulin mesylate in patients with solid tumours receiving repeated oral rifampicin.

Eribulin mesylate is a non‐taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours.

Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity

Chemotherapy-induced peripheral neuropathy is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities are unclear. At their MTDs, the microtubule-binding drugs paclitaxel and ixabepilone induce more severe neuropathy in mice relative to eribulin mesylate, paralleling their toxicity profiles in clinic. We hypothesized that the severity of their neurotoxic effects might be explained by the levels at which they accumulate in the peripheral nervous system. To test this hypothesis, we compared their pharmacokinetics and distribution in peripheral nerve tissue. After administration of a single intravenous dose, each drug was rapidly cleared from plasma but all persisted in the dorsal root ganglia (DRG) and sciatic nerve (SN) for up to 72 hours. Focusing on paclitaxel and eribulin, we performed a 2-week MTD-dosing regimen, followed by a determination of drug pharmacokinetics, tissue distribution, and multiple functional measures of peripheral nerve toxicity for 4 weeks. Consistent with the acute dosing study, both drugs persisted in peripheral nervous tissues for weeks, in contrast to their rapid clearance from plasma. Notably, although eribulin exhibited greater DRG and SN penetration than paclitaxel, the neurotoxicity observed functionally was consistently more severe with paclitaxel. Overall, our results argue that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity. Cancer Res; 76(11); 3332-9. ©2016 AACR.

Population pharmacometric analyses of eribulin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes

Pharmacometric investigation of eribulin was undertaken in patients with metastatic breast cancer (MBC) and other advanced solid tumors. A population pharmacokinetic (PK) model used data combined from seven phase 1 studies (advanced solid tumors; n = 129), and one phase 2 (MBC; n = 211), and one phase 3 study (MBC; n = 173). Phase 3 data were also used in a PK/pharmacodynamic (PD) model of efficacy and tumor response (sum of longest diameters of target lesions). All analyses used NONMEM 7.2. Eribulin PK, described by a dose‐independent, three‐compartment model with allometric relationship for body weight, was similar for all tumor types. Inter‐individual variability (IIV) was 52% for both exposure and clearance. Liver function markers (albumin, alkaline phosphatase, bilirubin) significantly influenced eribulin PK (7.3% of IIV in clearance). Tumor shrinkage correlated with eribulin exposure; a 36% decrease in tumor size from baseline was modeled at week 36. No patient/disease factors significantly predicted eribulins effect on tumor size. At week 6, a decrease in tumor size was associated with longer survival than an increase (P = .0055), suggesting survival may relate indirectly to eribulin exposure. These pharmacometric analyses provide a detailed overview of eribulin exposure–efficacy relationships to inform physicians treating patients with MBC.

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: Results of a phase 1 study

BackgroundThis phase 1 first-in-human study aimed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and safety of E6201, and to establish recommended dosing in patients with advanced solid tumours, expanded to advanced melanoma.MethodsPart A (dose escalation): sequential cohorts received E6201 intravenously (IV) over 30 min (once-weekly [qw; days (D)1 + 8 + 15 of a 28-day cycle]), starting at 20 mg/m2, increasing to 720 mg/m2 or the MTD. Part B (expansion): patients with BRAF-mutated or wild-type (WT) melanoma received E6201 320 mg/m2 IV over 60 minutes qw (D1 + 8 + 15 of a 28-day cycle) or 160 mg/m2 IV twice-weekly (D1 + 4 + 8 + 11 + 15 + 18 of a 28-day cycle; BRAF-mutated only).ResultsMTD in Part A (n = 25) was 320 mg/m2 qw, confirmed in Part B (n = 30). Adverse events included QT prolongation (n = 4) and eye disorders (n = 3). E6201 exposure was dose-related, with PK characterised by extensive distribution and fast elimination. One patient achieved PR during Part A (BRAF-mutated papillary thyroid cancer; 480 mg/m2 qw) and three during Part B (2 BRAF-mutated melanoma; 1 BRAF-WT melanoma; all receiving 320 mg/m2 qw).ConclusionsAn intermittent regimen of E6201 320 mg/m2 IV qw for the first 3 weeks of a 28-day cycle was feasible and reasonably well-tolerated in patients with advanced solid tumours, including melanoma with brain metastases, with evidence of clinical efficacy.

A phase 1 study of eribulin mesylate (E7389), a novel microtubule‐targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314)

Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose‐limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors.

Abstract 4503: Pharmacokinetics and pharmacodynamic analysis of eribulin mesylate and paclitaxel in mouse

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Neuropathy arising from chemotherapy (CIPN) is a major clinical problem representing the dose-limiting side effect of many antineoplastic drugs. At their respective MTDs, we previously reported paclitaxel and ixabepilone produced more severe deficits in nerve conduction velocity, amplitude and degenerative changes in dorsal root ganglia (DRG) and sciatic nerve (SN) versus eribulin mesylate (Wozniak et al 2011). Similar trends for eribulin to cause less neuropathy have also been reported in the clinic (Cigler and Vadhat 2010, Jain and Cigler 2012, Vadhat et al 2013). The underlying reason for this differential effect remains elusive. Differences in tubulin binding may, in part, explain the differential effect (Perez et al 2009, Jordan et al 2005). Another potential explanation could reside in different pharmacokinetic (PK) and nervous tissue distribution of these agents. Toward this latter point, we conducted tissue distribution and pharmacokinetic studies following acute dosing of eribulin mesylate, paclitaxel and ixabepilone. We reported that while all three drugs rapidly cleared from plasma, they distributed into and cleared slowly (>3 days) from peripheral nervous system tissues (Wozniak et al 2014). We have now extended these studies to look out to 42 days following both acute and 2 week MTD-dosing paradigms evaluating drug pharmacokinetics in plasma, DRG and SN as well as pharmacodynamic measurements of nerve conduction and amplitude. We found plasma levels of eribulin mesylate and paclitaxel rapidly declined over 24h after infusion. In contrast, the levels of eribulin mesylate and paclitaxel persisted at above quantification levels (ranging from 5-10 ng/g) for 7 to 14 days post cessation of 2 week MTD dosing. Eribulin mesylate consistently showed greater distribution into DRG and SN over paclitaxel. When comparing the induced nerve conduction deficits, we found paclitaxel and eribulin mesylate caused reduction of nerve conduction parameters similar to our previous studies, most notably in caudal nerve amplitude (by 80.5% and 54.9% respectively). However these deficits, which were sustained for up to several weeks after cessation of dosing, were more severe with paclitaxel. The findings demonstrate that despite eribulin mesylate showing higher nervous tissue distribution than paclitaxel, eribulin mesylate caused less neurotoxicity as evidenced by milder reductions in nerve conduction and amplitude. This work was financially supported by Eisai. Citation Format: Krystyna Wozniak, Ying Wu, Bruce A. Littlefield, Kenichi Nomoto, Christopher DesJardins, Yanke Yu, George Lai, Larisa Reyderman, Barbara S. Slusher. Pharmacokinetics and pharmacodynamic analysis of eribulin mesylate and paclitaxel in mouse. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4503. doi:10.1158/1538-7445.AM2015-4503

Abstract B193: Analysis of the concentration-QTc relationship for eribulin mesylate.

Introduction: Characterization of cardiac safety liability has become a critical part of clinical development plans for investigational drugs. For oncologic compounds, the standard “thorough QTc” study, which is typically conducted in healthy volunteers and includes placebo and a supratherapeutic dose, may not be possible due to drug toxicity. In the development of eribulin, a Phase 1 study was conducted to assess the potential effect of eribulin mesylate for QTc interval prolongation in female and male patients with recurrent and/or metastatic cancer. Results for two objectives are reported herein: to identify the more appropriate method of adjusting the QT interval for differences in heart rate (HR) and to develop an exposure-response model to characterize the relationship, if any, of time-matched change from baseline in QTc with exposure to eribulin. Methods: Subjects were administered 1.4 mg/m 2 of eribulin mesylate on Days 1 and 8 of a 21-day Study Phase. The dataset for the PK/PD analysis consisted of measured drug concentrations and QTcF values from triplicate 12-lead ECGs extracted from the continuous Holter. The timepoints in the study used in the PK/PD analysis were pre-dose, after eribulin infusion, and 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 10, 24, and 48 hours after the start of eribulin administration on Cycle 1 Days 1 and 8, with time-matched points for baseline from Day 0. In the correction of QT interval for HR, the Fridericia method (QTcF=QT/(RR) 0.33 ) was compared to an individually-derived method, QTcNi (QTcNi = QT + bi * (1000-RR), where RR is 60/(HR) and bi subject-specific slope). The performance of each correction algorithm was assessed via linear regression of individual subjects9 QTc versus RR intervals at on-treatment visits. The HR correction method with the mean of squared slopes closer to zero was preferred. The concentration-QTc relationship was assessed using a linear mixed effects analysis of the relationship between baseline-adjusted QTcF interval (QTcF) and observed eribulin mesylate concentration, according to the equation: QTcF = α + β * [eribulin], where interindividual variability was estimated for both intercept () and slope (). The effect of treatment period (i.e., Day 1 or Day 8) on slope and intercept was also evaluated. Consideration was also given to nonlinear relationships. Results: Both QTcF and QTcNi corrected for HR reasonably well, with QTcNi providing a correction that was less dependent on HR. The means of squared slopes for QTcF were 0.0097 and 0.0083 on Day 1 and Day 8, respectively, while corresponding means for QTcNi were 0.0053 and 0.0069. Development of mixed-effects models for both QTcF and QTcNi indicated no relationship with eribulin concentrations. The observed difference in typical QTc between Day 1 and Day 8, estimated as 5.7 msec for QTcNi and 7.6 msec for QTcF, was modeled with a fixed effect on the intercept. Within-subject residual deviation was modeled additively, with zero mean and estimated standard deviation of 13 msec. Conclusion: QTcNi was more effective than QTcF in removing the HR dependence of corrected QT values. No relationship was found between eribulin concentration and QTc. No QTc prolongation was observed on Day 1, whereas QTc values on Day 8 were small (9 msec) and independent of eribulin plasma concentration. A QTc interval increase of this magnitude is not expected to be of clinical concern in this subject population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B193.

Abstract 1294: Metabolism and excretion of eribulin in patients with advanced solid tumors

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL This Phase I, open-label, mass-balance study investigated the metabolism and excretion of eribulin, a non-taxane microtubule dynamics inhibitor with a novel mechanism of action, in patients with advanced solid tumors. A single 14C-eribulin acetate (∼85 μCi) 2 mg dose was given on Day 1 (cycle 1) as a 2-5-min IV bolus injection to 6 patients ≥18 years with advanced solid tumors that progressed after standard therapy or for which no standard therapy existed. Patients received 1.4 mg/m2 unlabeled eribulin mesylate (E7389) on Day 8 (cycle 1), and Days 1 and 8 of each subsequent 21-day cycle. Blood, urine, and fecal samples were collected from Days 1-8 (cycle 1) at specified time points or until sample radioactivity was <1% of the administered dose. Pharmacokinetic parameters were determined from plasma, urine, and fecal concentrations of unmetabolized eribulin and 14C-eribulin- derived material from Day 1 dosing. Mean plasma eribulin exposure (627 ng.hr/mL) was comparable to that of total radioactivity (568 ng equivalent.hr/mL). Time-matched concentration ratios of eribulin to total radioactivity approached unity in blood and plasma: unchanged parent compound constituted almost all eribulin-derived radioactivity. Few metabolites of eribulin were detected in plasma. Each metabolite represented <0.6% of eribulin indicating there were no major metabolites of eribulin in plasma. Elimination half-lives for eribulin (45.6 hr) and total radioactivity (42.3 hr) were comparable. Eribulin-derived radioactivity excreted in feces was slightly higher (mean 81.5%, range 60.2-101.2%) than that of unchanged eribulin (mean 61.9%, range 42.8-78.5%) indicating that unchanged eribulin was primarily excreted in feces. Renal clearance (0.301 L/hr) was a minor component of total eribulin clearance (3.93 L/hr). Eribulin-derived radioactivity excreted in urine was comparable (mean 8.9%, range 5.4-16.4%) to that of unchanged eribulin (mean 8.1%, range 5.0-15.3%), indicating minimal excretion of metabolite(s) in urine. Total recovery of the radioactive dose was 90.4% in urine and feces. Overall, no major metabolites of eribulin were detected in plasma. Eribulin is primarily eliminated unchanged in feces, while urine constitutes a minor route of elimination. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1294. doi:10.1158/1538-7445.AM2011-1294