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The pharmacokinetics of eribulin mesilate are characterized by a rapid distribution phase followed by a prolonged elimination phase, with a mean terminal half-life of approximately 40 h. It has a large volume of distribution (range of means 43 to 114l/m2). Eribulin mesilate is weakly bound to plasma proteins. The plasma protein binding of eribulin (100-1000 ng/ml) ranged from 49% to 65% in human plasma.
Unchanged eribulin mesilate was the major circulating species in plasma following administration of 14C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin.
Eribulin mesilate has a low clearance (range of means 1.16 to 2.42 l/h/m2). No significant accumulation of eribulin is observed on weekly administration. The pharmacokinetic properties are not dose or time dependent in the range of eribulin mesilate doses of 0.25 to 4.0 mg/m2.
Eribulin mesilate is eliminated primarily by biliary excretion. The transport protein involved in the excretion is presently unknown. Preclinical in vitro studies indicate that eribulin is transported by Pgp. However it has been shown that at clinically relevant concentrations eribulin is not a Pgp inhibitor in vitro. Additionally, in vivo, concomitant administration of ketoconazole, a Pgp inhibitor, has no effect on eribulin exposure (AUC and Cmax). In vitro studies have also indicated that eribulin is not a substrate for OCT1.
After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine indicating that renal clearance is not a significant route of eribulin elimination. Unchanged eribulin represented most of the total radioactivity in feces and urine.
A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=4) hepatic impairment due to liver metastases. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 3-fold in patients with mild and moderate hepatic impairment, respectively. Administration of Eribulin mesilate (Halaven) at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in a somewhat higher exposure than after a dose of 1.4 mg/m2 to patients with normal hepatic function. Eribulin mesylate (Halaven) was not studied in patients with severe hepatic impairment (Child-Pugh C). There is no study in patients with hepatic impairment due to cirrhosis. See DOSAGE AND ADMINISTRATION for dosage recommendation.
Increased eribulin exposure was seen in some patients with moderately or severely impaired renal function, with high between-subject variability. The pharmacokinetics of eribulin were evaluated in a Phase 1 study in patients with normal renal function (Creatinine clearance: ≥ 80 ml/min; n=6), moderate (30-50 ml/min; n=7) or severe (15-<30 ml/min; n=6) renal impairment. Creatinine clearance was estimated with the Cockcroft-Gault formula. A 1.5-fold
(90% CI: 0.9-2.5) higher dose-normalised AUC(0-inf) was observed in patients with moderate and severe renal impairment.See DOSAGE AND ADMINISTRATION for treatment recommendations.
Eribulin plasma concentrations were collected from 83 pediatric patients (age range: 2 to 17 years), with refractory/relapsed and recurrent solid tumours and lymphomas, who received eribulin in Studies 113, 213 and 223. Eribulin PK in pediatric patients was comparable to adult patients with STS and patients with other types of tumour. Eribulin exposure in pediatric patients was similar to exposure in adult patients. Concomitant irinotecan did not have an effect on eribulin PK in pediatric patients with refractory/relapsed and recurrent solid tumours.