Influence of hepatic impairment on lenvatinib pharmacokinetics following single‐dose oral administration

Shumaker, Robert; Aluri, Jagadeesh; Fan, Jean; Martinez, Gresel; Pentikis, Helen S.; Ren, Min

doi:10.1002/jcph.398

Cited by 50 publications

(37 citation statements)

References 27 publications

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“…After administration of a single dose, the C max of 12 mg lenvatinib in the CP-A group was similar to that in patients with solid tumors who received a 12 mg dose, but lower than in those who received 25 mg. However, since lenvatinib oral clearance after administration of multiple doses in patients with HCC was decreased in this study, the C 24 h of 12 mg in the CP-A group was higher than that in patients with solid tumors who received 12 mg lenvatinib, and was comparable to that of those who received 25 mg. Shumaker and colleagues (31) showed that lenvatinib AUCs and oral clearance were similar for single-dose administration between healthy subjects and those with mild (CP-A) or moderate (CP-B) hepatic impairment. The reason for the discrepancy in PK outcomes related to hepatic impairment between subjects without HCC and patients with HCC is unknown, but may result from differences in underlying hepatic etiology (32).…”

Section: Discussionmentioning

confidence: 98%

Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Ikeda

Okusaka

Mitsunaga

et al. 2016

Clinical Cancer Research

168

139

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Purpose: To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC).Experimental Design: This multicenter, open-label, phase I, dose-escalation study included patients aged 20 to 80 years, refractory to standard therapy, and stratified by hepatic function measured using Child-Pugh (CP) scores: CP-A (score, 5-6) and CP-B (score, 7-8). Lenvatinib was administered continually once daily for 4-week cycles. MTD was defined as the maximum dose associated with 1 dose-limiting toxicity (DLT) occurring in cycle 1 among 6 patients.Results: In total, 20 patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most common grade 3 toxicities included hypertension in CP-A and hyperbilirubinemia in CP-B. Lenvatinib plasma concentration at 24 hours after administration (C 24 h ) for 12 mg once daily was higher in patients with HCC than in patients with other solid tumors shown in a previous phase I study, but C 24 h for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit þ cells decreased and the levels of interleukin (IL)-6, IL10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (P < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients. Conclusions: Lenvatinib (12 mg once daily) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase II studies in patients with HCC and CP-A.

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Section: Discussionmentioning

confidence: 98%

Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Ikeda

Okusaka

Mitsunaga

et al. 2016

Clinical Cancer Research

168

139

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“…The influence of body weight on the pharmacodynamics of antiangiogenic agents and resultant toxicity patterns is still uncertain [26]. Additionally, increased lenvatinib exposure was found in patients with severe hepatic impairment [27]. It is possible that in patients with HCC, who typically have impaired hepatic function, lenvatinib PK is more affected by body weight than in healthy individuals or patients with other cancers.…”

Section: Discussionmentioning

confidence: 99%

Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma

et al. 2016

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BackgroundLenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, RET, and KIT. This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC).MethodsPatients with histologically/clinically confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles. The primary efficacy endpoint was time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors v1.1; secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS).ResultsBetween July 2010 and June 2011, 46 patients received lenvatinib at sites across Japan and Korea. The median TTP, as determined by independent radiological review, was 7.4 months [95 % confidence interval (CI): 5.5–9.4]. Seventeen patients (37 %) had partial response and 19 patients (41 %) had stable disease (ORR: 37 %; DCR: 78 %). Median OS was 18.7 months (95 % CI: 12.7–25.1). The most common any-grade adverse events (AEs) were hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61 %), and proteinuria (61 %). Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively. Median body weight was lower in patients with an early (<30 days) dose withdrawal or reduction than in those without.ConclusionsLenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight. Further development of lenvatinib in HCC should consider dose modification by body weight.Trial registration ID www.ClinicalTrials.gov NCT00946153.Electronic supplementary materialThe online version of this article (doi:10.1007/s00535-016-1263-4) contains supplementary material, which is available to authorized users.

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“…This mass balance study therefore warrants to further examine the effect of renal and hepatic impairment on the pharmacokinetics of lenvatinib, and clinical trials to investigate this have been performed. The results of a hepatic impairment trial were recently published by Shumaker et al and led to the conclusion that a reduced dose is advisable for subjects with severe hepatic impairment [17].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

et al. 2014

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Summary Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of 14 Clenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.

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Influence of hepatic impairment on lenvatinib pharmacokinetics following single‐dose oral administration

Cited by 50 publications

References 27 publications

Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

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