Impact of Local Liver Irradiation Concurrent Versus Sequential with Lenvatinib on Pharmacokinetics and Biodistribution

Tsai, Tung Hu; Chen, Yu-Jen; Wang, Li Ying; Hsieh, Chen‐Hsi

doi:10.3390/cancers13071598

Cited by 5 publications

(6 citation statements)

References 55 publications

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“…Moreover, the primary sources of ROS in the liver are the mitochondria and cytochrome P450 enzyme systems and derive from Kupffer and inflammatory cells ( 15 ). Additionally, drug pharmacokinetics influenced by RT has previously been revealed ( 16 , 17 ). Breast cancer patients treated by advanced RT could experience off-target exposure to surrounding organs such as the lung and heart, which might cause unpredictable effects ( 18 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

“…Breast cancer patients treated by advanced RT could experience off-target exposure to surrounding organs such as the lung and heart, which might cause unpredictable effects ( 18 , 19 ). Recently, RT significantly impacted the hepatic microsomal cytochrome P450 3A4 (CYP3A4) activity and P-glycoprotein (P-gp) activity ( 16 , 17 ). This was likely caused by an unintended interaction between RT and tamoxifen.…”

Section: Introductionmentioning

confidence: 99%

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Impact of Irradiation on the Pharmacokinetics and Biotransformation of Tamoxifen

et al. 2022

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BackgroundThe optimal procedure for combining radiotherapy (RT) with tamoxifen treatment is controversial as RT may alter the pharmacokinetics and biotransformation of tamoxifen. The present study investigated this potential interaction by assessing the pharmacokinetics of tamoxifen during concurrent and sequential RT.MethodPlasma tamoxifen concentration was measured in rats with or without RT 2.0 Gy (RT2.0Gy) or 0.5 Gy (RT0.5Gy) with ultra-high-performance liquid chromatography-tandem mass spectrometry after tamoxifen administration (10 mg/kg, p.o., n = 6). Tamoxifen was either administered 1 h after RT (concurrent condition) or 24 h after RT (sequential condition).ResultsPharmacokinetic data analysis demonstrated that the area under the curve (AUC) and half-life of tamoxifen were 2,004 ± 241 h ng/ml and 6.23 ± 1.21 h, respectively, after tamoxifen administration (10 mg/kg, p.o.). The respective conversion rate of 4-hydroxytamoxifen, N-desmethytamoxifen, and endoxifen for tamoxifen metabolism was 20%, 16%, and 5%. The AUC value of tamoxifen in the RT0.5Gy group was 1.5- to 1.7-fold higher than in the sham and RT2.0Gy groups. The relative bioavailability of tamoxifen at concurrent RT0.5Gy and RT2.0Gy groups ranged from 127% to 202% and from 71% to 152%, respectively. The magnitude of endoxifen, which converted from 4-hydroxytamoxifen and N-desmethyltamoxifen, increased 3- to 5-fold in the concurrent RT groups. By contrast, the AUC of tamoxifen decreased by roughly 24% in the sequential RT2.0Gy group. The conversion ratio of endoxifen was four times higher than that in the sequential RT2.0Gy group compared with rats not exposed to RT.ConclusionThe current study provides advanced pharmacokinetic data to confirm the interaction between RT and hormone therapy. Our findings indicate that RT facilitates the metabolism of tamoxifen to active metabolites and thus imply that combination RT-tamoxifen has potential benefits for the treatment of hormone-dependent breast cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of Irradiation on the Pharmacokinetics and Biotransformation of Tamoxifen

et al. 2022

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“…Recently, Dawson et al [ 20 ] reported that SBRT followed by sorafenib improved the overall survival, progression-free survival and time to disease progression compared with sorafenib alone for HCC patient. Moreover, our previous data showed that RT modulated PK of TKIs [ 19 , 21 , 22 ] and supported the interaction between RT and TKIs.…”

Section: Introductionmentioning

confidence: 55%

“…Similarly, the AUC of regorafenib was increased 1.3-fold in the sequential RT 9Gyx3f’x group [ 21 ]. The AUC of lenvatinib was increased 2-fold in the sequential RT 9Gyx3f’x group [ 22 ]. The lines of evidence support the interaction between RT and TKIs.…”

Section: Discussionmentioning

confidence: 99%

Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats

Huang

Hsieh

Wang

et al. 2023

IJMS

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The aim of this study was to evaluate the radiotherapy (RT)-pharmacokinetics (PK) effect of cabozantinib in concurrent or sequential regimens with external beam radiotherapy (EBRT) or stereotactic body radiation therapy (SBRT). Concurrent and sequential regimens involving RT and cabozantinib were designed. The RT–drug interactions of cabozantinib under RT were confirmed in a free-moving rat model. The drugs were separated on an Agilent ZORBAX SB-phenyl column with a mobile phase consisting of 10 mM potassium dihydrogen phosphate (KH2PO4)–methanol solution (27:73, v/v) for cabozantinib. There were no statistically significant differences in the concentration versus time curve of cabozantinib (AUCcabozantinib) between the control group and the RT2Gy×3 f’x and RT9Gy×3 f’x groups in the concurrent and the sequential regimens. However, compared to those in the control group, the Tmax, T1/2 and MRT decreased by 72.8% (p = 0.04), 49.0% (p = 0.04) and 48.5% (p = 0.04) with RT2Gy×3 f’x in the concurrent regimen, respectively. Additionally, the T1/2 and MRT decreased by 58.8% (p = 0.01) and 57.8% (p = 0.01) in the concurrent RT9Gy×3 f’x group when compared with the control group, respectively. The biodistribution of cabozantinib in the heart increased by 271.4% (p = 0.04) and 120.0% (p = 0.04) with RT2Gy×3 f’x in the concurrent and sequential regimens compared to the concurrent regimen, respectively. Additionally, the biodistribution of cabozantinib in the heart increased by 107.1% (p = 0.01) with the RT9Gy×3 f’x sequential regimen. Compared to the RT9Gy×3 f’x concurrent regimen, the RT9Gy×3 f’x sequential regimen increased the biodistribution of cabozantinib in the heart (81.3%, p = 0.02), liver (110.5%, p = 0.02), lung (125%, p = 0.004) and kidneys (87.5%, p = 0.048). No cabozantinib was detected in the brain in any of the groups. The AUC of cabozantinib is not modulated by irradiation and is not affected by treatment strategies. However, the biodistribution of cabozantinib in the heart is modulated by off-target irradiation and SBRT doses simultaneously. The impact of the biodistribution of cabozantinib with RT9Gy×3 f’x is more significant with the sequential regimen than with the concurrent regimen.

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“…The study by Wild et al [ 36 ] demonstrated that sequential sorafenib treatment after radiotherapy appears to be more effective for HCC. For lenvatinib combined with radiotherapy, a study of the pharmacokinetic and biodistribution effects of simultaneous or sequential lenvatinib with local liver irradiation in a freely moving rat model [ 37 ] demonstrated that a sequential regimen has a greater ability to maintain lenvatinib uptake compared to a simultaneous regimen, and that sequential regimens may be more impactful than concurrent regimens. However, there are fewer studies on the sequence of radiotherapy combined with TKIs, and further evidence is needed to elucidate the impact of the sequence between the two on treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

Lenvatinib with or without stereotactic body radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis: a retrospective study

Ji¹,

Xu²,

Sun³

et al. 2023

Radiat Oncol

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Background and objectives Patients with hepatocellular carcinoma (HCC) involving portal vein tumor thrombosis (PVTT) are presently lacking effective treatment options. We aimed to compare the efficacy and safety of lenvatinib with or without SBRT for HCC with PVTT. Materials and methods This retrospective analysis included 37 patients treated with lenvatinib in combination with SBRT and 77 patients treated with lenvatinib alone from August 2018 to August 2021. Overall survival (OS), progression-free survival (PFS), intrahepatic PFS (IHPFS) and objective remission rate (ORR) were compared between the two groups, while adverse events (AEs) was analyzed between the two groups to assess safety profiles. Results Median OS, PFS and IHPFS were significantly prolonged in the combination treatment group compared with the single treatment group (median OS, 19.3 vs. 11.2 months, p < 0.001; median PFS: 10.3 vs. 5.3 months, p < 0.001; median IHPFS, 10.7 vs. 5.3 months, p < 0.001). Moreover, a higher ORR (56.8% vs. 20.8%, P < 0.001) were observed in the lenvatinib combined with SBRT group. In subgroup analyses of Vp1-2 and Vp3-4 group, median OS, PFS and IHPFS were also significantly longer in the lenvatinib combined with SBRT group than those in the lenvatinib alone group. AEs in the combined therapy group were mostly manageable and the incidence was not statistically significant compared to the monotherapy group. Conclusion Lenvatinib plus SBRT had a significantly better survival benefit than lenvatinib monotherapy in the treatment of HCC patients with PVTT and was well tolerated.

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Impact of Local Liver Irradiation Concurrent Versus Sequential with Lenvatinib on Pharmacokinetics and Biodistribution

Cited by 5 publications

References 55 publications

Impact of Irradiation on the Pharmacokinetics and Biotransformation of Tamoxifen

Impact of Irradiation on the Pharmacokinetics and Biotransformation of Tamoxifen

Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats

Lenvatinib with or without stereotactic body radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis: a retrospective study

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