A phase I study investigation of metabolism, and disposition of [14C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

Liu, Lianke; Liu, Lingxiang; Wang, Tongshan; Guo, Lian; Wang, Yixiang; Gao, Zhengzhen; Shu, Yongqian

doi:10.1007/s00280-020-04062-8

Cited by 10 publications

(7 citation statements)

References 15 publications

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“… 18 The results showed that the combination of chemotherapy and anlotinib could improve the survival rate of patients with advanced/metastatic STS and was well tolerated. Liu et al 32 analyzed the data from 21 adults with unresectable or metastatic STS who were retrospectively diagnosed. The results indicated that switching maintenance therapy with anlotinib is a promising strategy for treating patients with unresectable or metastatic STS who have undergone chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Efficacy and Safety of Anlotinib as a Monotherapy and Combined Therapy for Advanced Sarcoma

Yao¹,

Du²,

Wang³

et al. 2022

OTT

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Objective To analyze the effectiveness of the long-term (> 12 months) administration of anlotinib as a monotherapy or combined therapy in patients with advanced sarcomas. Methods A retrospective analysis was conducted of patients with advanced sarcomas with measurable target lesions since 2018. Twenty-two of the patients had taken anlotinib regularly for > 12 months. The patients’ general information and the drug’s clinical efficacy and toxicity data were collected and statistically analyzed using RECIST 1.1 to measure the target lesions and tumor PFS time as the main endpoints. We used a swimmer plot to observe the drug’s efficacy and duration, and employed a waterfall plot to express the best treatment effect. Results The study included 14 male and 8 female patients, ranging in age from 14 to 75 (mean: 44.82) years. The primary diseases included alveolar soft part sarcoma, synovial sarcoma, leiomyosarcoma, and others. The metastasis sites were the lungs in fifteen cases, lymph nodes in four cases, and multiple sites in three cases. Fourteen patients had previously undergone chemotherapy. The current therapy protocol was oral anlotinib alone for nine cases, combination chemotherapy for nine cases, and combination immunotherapy (anti-PD-1) for four cases. The highest clinical efficacy was complete remission (CR) in four (18.18%) cases, partial response (PR) in five (22.73%) cases, and stable disease in 13 (59.09%) cases, with an odds ratio of response of 40.91%. The mean PFS for the CR, PR, and stable disease groups was 16.50, 14.50, and 29.31 months, respectively (p < 0.05). The main adverse effects included hand-foot syndrome, hypertension, and leukopenia. Conclusion Anlotinib monotherapy or combination therapy can be more effective and safer for certain advanced sarcomas, with more extended maintenance and acceptable side effects. Clinical efficacy at the CR and PR levels might predict the long-term PFS in certain advanced sarcomas.

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Section: Discussionmentioning

confidence: 99%

Long-Term Efficacy and Safety of Anlotinib as a Monotherapy and Combined Therapy for Advanced Sarcoma

Yao¹,

Du²,

Wang³

et al. 2022

OTT

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“…Liu et al. focused on the detailed absorption, metabolism, and excretion pathways of anlotinib ( 73 ). Analysis showed that anlotinib was absorbed rapidly, had a long half-life, and underwent long and extensive hepatic metabolism, which is a good PK profile.…”

Section: Clinical Trials Of Anlotinib In Advanced Sts and Osteosarcomamentioning

confidence: 99%

“…The results indicated that switch maintenance therapy with anlotinib is a promising strategy for the treatment of patients with unresectable or metastatic STS who have received chemotherapy. Liu et al focused on the detailed absorption, metabolism, and excretion pathways of anlotinib (73). Analysis showed that anlotinib was absorbed rapidly, had a long half-life, and underwent long and extensive hepatic metabolism, which is a good PK profile.…”

Section: Clinical Trials Of Anlotinib In Advanced Sts and Osteosarcomamentioning

confidence: 99%

Anlotinib: A Novel Targeted Drug for Bone and Soft Tissue Sarcoma

2021

Front. Oncol.

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Bone and soft tissue sarcomas account for approximately 15% of pediatric solid malignant tumors and 1% of adult solid malignant tumors. There are over 50 subtypes of sarcomas, each of which is notably heterogeneous and manifested by remarkable phenotypic and morphological variability. Anlotinib is a novel oral tyrosine kinase inhibitor (TKI) targeting c-kit, platelet-derived growth factor receptors, fibroblast growth factor receptor, and vascular endothelial growth factor receptor. In comparison with the placebo, anlotinib was associated with better overall survival and progression-free survival (PFS) in a phase III trial of patients with advanced non-small cell lung cancer (NSCLC), albeit with cancer progression after two previous lines of treatment. Recently, the National Medical Products Administration approved anlotinib monotherapy as a third-line treatment for patients with advanced NSCLC. Additionally, a phase IIB randomized trial substantiated that anlotinib is associated with a significant longer median PFS in patients with advanced soft tissue sarcoma. Moreover, anlotinib is also effective in patients with advanced medullary thyroid carcinoma and metastatic renal cell carcinoma. Anlotinib has similar tolerability to other TKIs targeting vascular endothelial growth factor receptors and other tyrosine kinase-mediated pathways. However, anlotinib has a notably lower rate of side effects ≥grade 3 relative to sunitinib. This review discussed the remarkable characteristics and major dilemmas of anlotinib as a targeted therapy for sarcomas.

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“…It has a large apparent volume of distribution (V) and a long half-life (t 1/2 ) of 96 ± 17 h [9,10]. Anlotinib was mainly eliminated by extensive hepatic metabolism mediated by cytochrome P450 and primarily excreted in feces and urine [11]. Besides, anlotinib exposure showed a moderate to high inter-or intra-individual variability in previous study [9].…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic and Covariate Analysis of Anlotinib in Patients with Malignant Tumors

Yang

Shen

et al. 2022

Preprint

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Purpose The objective of this study was to develop a population pharmacokinetic (popPK) model of anlotinib and to investigate the impact of various covariates in patients with malignant tumors. Methods A total of 407 anlotinib plasma concentrations from 16 patients were analyzed in this study. Anlotinib was administered orally 12 or 16 mg in the single-dose phase and 12 mg once daily in the multiple-dose phase. PopPK model was established using nonlinear mixed-effects model (NONMEM) method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetic was investigated in a covariate analysis. The final model was evaluated using goodness-of-fit plots, visual predictive check, and bootstrap methods. Results The pharmacokinetic profile of anlotinib was best described by a one-compartment model with first-order absorption and linear elimination. The population estimates of the apparent total clearance (CL/F), apparent volume of distribution (V/F) and absorption rate constant (Ka) were 8.91 L/h, 1950 L and 0.745 h-1, respectively. Body weight was identified as a significant covariate on V/F. Patients with low body weight tended to show higher exposure to anlotinib than those with high body weight. However, these differences were not clinically significant in the simulations of the individual body weight effects. No obvious bias was found in the final model by bootstrap and VPC methods. Conclusion This popPK model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors. Anlotinib does not need any dose modifications since the effect size for the individual covariate is not considered clinically relevant with anlotinib exposure.

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A phase I study investigation of metabolism, and disposition of [14C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

Cited by 10 publications

References 15 publications

Long-Term Efficacy and Safety of Anlotinib as a Monotherapy and Combined Therapy for Advanced Sarcoma

Long-Term Efficacy and Safety of Anlotinib as a Monotherapy and Combined Therapy for Advanced Sarcoma

Anlotinib: A Novel Targeted Drug for Bone and Soft Tissue Sarcoma

Population Pharmacokinetic and Covariate Analysis of Anlotinib in Patients with Malignant Tumors

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