Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy

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Hepatocellular carcinoma, the most common form of liver cancer, is the third leading cause of cancer-related deaths. The number of cases is expected to double by 2040, according to GLOBOCAN 2020. Patients are usually diagnosed with advanced-stage HCC, which limits the number of effective treatment options. Oral-targeted therapies involving sorafenib and lenvatinib remain the first-line treatment option, which has recently been replaced by immunotherapy. Due to economic issues and ease of administration, the vast majority prefer oral systemic therapy. Sorafenib and lenvatinib, which belongs to tyrosine kinase inhibitors have few limitations of having large inter-individual variability in absorption, genetic polymorphisms, poor patient adherence to oral regimen limiting its long-term therapy. Therapeutic Drug Monitoring can overcome the limitations of TKIs and help individualise the dosage regimen with minimal adverse events. Therefore, this simple and rapid method using latest equipment enabled with ultra-high speed, high-sensitivity analysis (LCMS-8045) is expected to bring a change in clinical practice to improve the efficacy and safety of medication for optimal patient benefits." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-1334/v1", "name": "Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular..." } } ] } Home Browse Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Babu M, Sadasivan S, T P A et al. Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :1334 ( https://doi.org/10.12688/f1000research.153153.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] Merin Babu https://orcid.org/0000-0002-3384-6497 1 , Shine Sadasivan 2 , Aneesh T P 3 , [...] Teun Van Gelder 4 , Shiny Thomas 5 , C T Aravindkumar 5 , Niveditha Kartha 6 , Keechilat Pavithran https://orcid.org/0000-0002-6129-5709 1 Merin Babu https://orcid.org/0000-0002-3384-6497 1 , Shine Sadasivan 2 , [...] Aneesh T P 3 , Teun Van Gelder 4 , Shiny Thomas 5 , C T Aravindkumar 5 , Niveditha Kartha 6 , Keechilat Pavithran https://orcid.org/0000-0002-6129-5709 1 PUBLISHED 07 Nov 2024 Author details Author details 1 Medical Oncology, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, 682041, India 2 Gastroenterology, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, 682041, India 3 Pharmaceutical Chemistry and Analysis, Amrita Vishwa Vidyapeetham, Amrita School of Pharmacy, AIMS Health Science Campus, Kochi, Kerala, 682041, India 4 Clinical Pharmacy and Toxicology, Leiden University, Leiden University Medical Center, Netherlands, 9500 2300, Netherlands Antilles 5 Sophisticated Analytical Instrument Facility (DST-SAIF), Mahatma Gandhi University, Kottayam, Kerala, 686560, India 6 Biostatistics, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, 682041, India Merin Babu Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Project Administration, Resources, Validation, Writing – Original Draft Preparation Shine Sadasivan Roles: Conceptualization, Funding Acquisition, Supervision, Writing – Review & Editing Aneesh T P Roles: Conceptualization, Formal Analysis, Methodology, Supervision, Writing – Review & Editing Teun Van Gelder Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Shiny Thomas Roles: Formal Analysis, Methodology, Validation, Writing – Review & Editing C T Aravindkumar Roles: Formal Analysis, Resources, Supervision, Writing – Review & Editing Niveditha Kartha Roles: Formal Analysis, Resources Keechilat Pavithran Roles: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Cancer remains a public concern and leading cause of death worldwide. Hepatocellular carcinoma, the most common form of liver cancer, is the third leading cause of cancer-related deaths. The number of cases is expected to double by 2040, according to GLOBOCAN 2020. Patients are usually diagnosed with advanced-stage HCC, which limits the number of effective treatment options. Oral-targeted therapies involving sorafenib and lenvatinib remain the first-line treatment option, which has recently been replaced by immunotherapy. Due to economic issues and ease of administration, the vast majority prefer oral systemic therapy. Sorafenib and lenvatinib, which belongs to tyrosine kinase inhibitors have few limitations of having large inter-individual variability in absorption, genetic polymorphisms, poor patient adherence to oral regimen limiting its long-term therapy. Therapeutic Drug Monitoring can overcome the limitations of TKIs and help individualise the dosage regimen with minimal adverse events. Therefore, this simple and rapid method using latest equipment enabled with ultra-high speed, high-sensitivity analysis (LCMS-8045) is expected to bring a change in clinical practice to improve the efficacy and safety of medication for optimal patient benefits. READ ALL READ LESS Keywords Sorafenib, Lenvatinib, Precision medicine, Hepatocellular Carcinoma Corresponding Author(s) Keechilat Pavithran ( [email protected] ) Close Corresponding author: Keechilat Pavithran Competing interests: No competing interests were disclosed. Grant information: This work was supported by a grant from the Indian Council of Medical Research (ICMR) Extramural Ad-hoc scheme [Project ID: 2020-9645GIA/2019/000399/PRCGIA] and sanctioned by Dr. K Pavithran. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Babu M et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Babu M, Sadasivan S, T P A et al. Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :1334 ( https://doi.org/10.12688/f1000research.153153.1 ) First published: 07 Nov 2024, 13 :1334 ( https://doi.org/10.12688/f1000research.153153.1 ) Latest published: 04 Jul 2026, 13 :1334 ( https://doi.org/10.12688/f1000research.153153.2 )  There is a newer version of this article available. Suppress this message for one day. Introduction Globally, cancer is a significant public health issue and a leading cause of death. 1 Global Cancer Observatory (GLOBOCAN) estimates for 2020 indicate that 19.3 million cancer cases have occurred globally. India ranked third after China and the United States. According to GLOBOCAN’s prediction, the number of cancer cases in India is expected to rise to 2.09 million by 2040, representing a 57.5% increase from 2020. 2 Hepatocellular carcinoma (HCC) is the most frequently occurring tumor among all primary liver cancers, accounting for 75–85% of cases. Patients with HCC are typically treated at an advanced stage, when a limited number of effective treatment options are available. Patients with advanced stages of HCC may benefit from systemic therapy. 3 – 5 Despite improvements in early stage prognosis, the survival rate of patients with advanced illness remains poor. Sorafenib and lenvatinib, tyrosine kinase inhibitors (TKIs), have been the first-line treatments for advanced HCC throughout the last decade, improving overall survival and quality of life, and have recently been replaced by immunotherapy. 6 , 7 Sorafenib, a multiple-target tyrosine kinase inhibitor (TKI), inhibits angiogenesis by targeting proteins such as PDGFR-β, VEGFR-2, and c-KIT, and proliferation by targeting Raf-1, B-Raf, and kinase activity in the Ras/Raf/MEK/ERK signalling pathways, while extending the overall median survival of patients with advanced HCC. 8 According to the US Food and Drug Administration (FDA) recommendation, the approved dose of sorafenib is 400 mg (two tablets) twice daily without food. The dose may be reduced to 400 mg once daily depending on the adverse drug reactions experienced, such as hypertension, fatigue, weight loss, rash, hand-foot skin reaction, alopecia, and pruritus. 9 Lenvatinib, a multi-targeted receptor kinase inhibitor, inhibits the activity of FGFR 1, 2, 3, and 4; PDGFR α; VEGFR 1, 2, and 3; RET; and KIT. Lenvatinib binds to receptors and inhibits the PLCγ, Ras-Raf-ERK, and PI3K-AKT pathways, arresting tumor angiogenesis and cell death. 10 The median overall survival was 10.7 months in the sorafenib versus 12.8 months in lenvatinib group. 11 , 12 Lenvatinib significantly surpassed sorafenib in terms of the ORR, PFS, and TTP. Its tolerance is adequate, and the most common adverse events (AEs) associated with therapy are hypertension, diarrhea, lack of appetite, and weight loss. 13 Poor adherence to oral chemotherapy is another major factor limiting long-term therapy. Inter-individual variability in pharmacokinetics is particularly pertinent in oncology, as anticancer agents are frequently administered at doses close to the maximally tolerable intensity, and most TKIs are considered to have a narrow therapeutic index. 14 Therefore, individualized dosing guided by pharmacokinetics could lead to less underdosing and reduced toxicity rates owing to overdosing. 15 Therapeutic Drug Monitoring (TDM) involves individualized drug dosage by maintaining plasma or drug concentrations within a therapeutic range or window. This clinical practice enables assessment of the efficacy and safety of medications for optimal patient benefits. 16 Determining sorafenib and lenvatinib plasma concentrations helps provide individualized treatment through dose adjustments to improve efficacy and avoid adverse effects. Generally, Asian patients do not tolerate the recommended dose in Western patients. 17 – 19 According to FDA recommendations, sorafenib 400 mg (two tablets) twice daily and lenvatinib according to body weight (8 mg once daily if weight < 60 kg; 12 mg once daily if weight ≥ 12 kg), only a few patients can tolerate the total dose. Our preliminary data show that even at 25% or 50% of the recommended doses, therapeutic levels are achieved with a minimal adverse effects profile, and better patient adherence can increase quality of life. Rationale of the study Achieving maximum therapeutic efficacy with minimal iatrogenic toxicity is the primary objective of pharmacological treatment of patients with cancer. To achieve this goal, the dosage regimen should be adjusted for each patient. In regular clinical practice, although some individuals respond well to the standardized drug dosage regimen, others may experience lower efficacy and adverse effects. 20 The association between dosage regimens and changes in drug and/or metabolite concentrations throughout the body over time has been studied using pharmacokinetics. 21 Dose adaptation based on therapeutic drug concentration, that is, therapeutic drug monitoring, can improve the treatment quality. Although TDM is routinely used for antibiotics and immunosuppressants, its role in the treatment of cancer is underutilized. 16 The criteria that need to be considered as candidates for TDM are tyrosine kinase inhibitors, which include large inter-individual PK variability, variable absorption rates, genetic variations in metabolizing enzymes, and interactions among co-medications. 22 – 24 TKIs are mostly oral drugs that block the binding site of adenosine triphosphate (ATP) of tyrosine kinase receptors in malignant cells, thus preventing autophosphorylation of tyrosine residues and activating proteins involved in angiogenesis and tumor proliferation signalling pathways. 25 TKIs are usually administered at fixed doses 26 and orally. Steady-state methods provide a wide range of plasma concentrations with an inter-individual variability in trough concentration (C trough ) of up to23-fold. Sorafenib, an oral multi-kinase inhibitor with a recommended dosage of 400 mg twice daily, is a highly plasma-bound drug (99.5%). The liver metabolizes sorafenib via CYP3A4 enzyme and glucuronidation. High-fat meals reduce the bioavailability of sorafenib; therefore, they are either administered one hour before food or two hours after food intake. Close monitoring of patients receiving sorafenib therapy is required to determine toxicities. 8 , 27 , 28 According to previous studies and our pilot study, sorafenib concentrations ranged from 3.6 to 7 μg/mL. Improved overall survival was seen in patients with maximum sorafenib concentration C max ≥4.78 μg/mL. 29 – 31 The multi-targeted inhibitor lenvatinib was approved at 12 mg/day for patients with a body weight ≥ 60 kg and 8 mg/day for patients with a body weight < 60 kg. The drug is rapidly absorbed orally within 1-4 hours of administration (T max ). The enzymes CYP3A4 metabolize lenvatinib and are excreted in feces. Ninety-six to ninety-eight percent of the drug proteins are protein-bound. The incidence of gastrointestinal and skin toxicities is closely related to the concentration of lenvatinib. 32 , 33 A study by Noda et al. 34 demonstrated that lenvatinib’s target trough concentration in the treatment of HCC may range from 36.8 to 71.4 ng/mL in order to control disease and minimize grade 3 toxicity. Although the relationship between sorafenib and lenvatinib exposure and toxicity has been reported, data from the Indian population are lacking. Here, we describe a sensitive, rapid, and simple LC-MS/MS method for the analysis of sorafenib and lenvatinib in human plasma using simple mobile phases (water and acetonitrile) with 0.1% formic acid, and extraction of analytes by simple protein precipitation with acetonitrile. The developed method reports a precise LC-MS/MS approach for the determination of sorafenib, sorafenib-n-oxide, and lenvatinib in hepatocellular carcinoma patients. Primary outcomes To elucidate the association between plasma sorafenib and lenvatinib concentrations and their clinical efficacy in patients with HCC at a tertiary care hospital. Secondary outcomes 1. To develop and validate a method for the quantification of plasma sorafenib, sorafenib N-oxide, and lenvatinib concentrations. 2. To study the relationship between trough plasma concentrations of sorafenib and lenvatinib and their clinical responses. 3. To study the relationship between trough plasma concentrations of sorafenib, sorafenib N-oxide, and lenvatinib and adverse effects. 4. To determine the efficacy parameters and correlation of trough concentrations of sorafenib and lenvatinib with treatment efficacy, patients will be analyzed for tumor response using the mRECIST criteria: (a) complete response; (b) partial response; (c) stable disease; (d) progressive disease; (e) objective response rate; and (f) disease control rate (DCR). 5. To determine the overall survival (OS) and progression-free survival (PFS) of patients treated with sorafenib and lenvatinib, the Child-Pugh class A and B groups (severity of disease) were analyzed. Methods For three years, this prospective, interventional study was conducted in the Department of Medical Oncology, Amrita Institute of Medical Sciences, Kochi. The study protocol was approved by the Ethics Committee of Amrita School of Medicine (ECASM-AIMS-2021-293) on 15-06-2021 and was conducted as per principles of the Declaration of Helsinki and guidelines of the Indian Council of Medical Research. Study population The study population includes patients visiting the Medical Oncology Department of AIMS and were diagnosed with unresectable hepatocellular carcinoma treated with sorafenib and lenvatinib. Inclusion criteria To be eligible for inclusion in this study, participants must meet the following criteria: (a) an adult patient diagnosed with unresectable hepatocellular carcinoma; (b) Patients with Child-Pugh scores of A and B; (c) Patients with Barcelona Clinic Liver Cancer (BCLC B) and (BCLC C); (d) patients who had a good performance status (ECOG-PS: 0-2); and (e) patients or their caregivers willing to provide informed signed consent. Exclusion criteria The exclusion criteria were as follows: (a) incomplete patient data profile, (b) neurological or psychiatric conditions, and (c) decompensated liver cirrhosis. Data collection Demographic, initial presenting symptoms, laboratory, staging, and radiological details will be collected using the Amrita Hospital Information System (AHIS) [Amrita Hospital, Kochi]. The adverse events profilewill be monitored during each visit through verbal communication. The sorafenib and lenvatinib drug concentrations will be determined using LC-MS/MS apparatus (Shimadzu LCMS-8045, Japan) of Sophisticated Analytical Instrument Facility (Mahatma Gandhi University, Kottayam). Procedure The following steps will be- (a) Stock solution preparation • A weighed quantity (2.5 mg) of sorafenib/sorafenib-N-oxide/lenvatinib API [Clearsynth Lab Ltd, Chennai] will be dissolved in a suitable solvent (10 mL of 0.1% formic acid in water and acetonitrile) [Nice Chemicals, Kochi, Kerala] to obtain a stock concentration of 250 ppb. The stock solution will be then sonicated, filtered, and different concentrations 10,20,40,80 and 100 ppb will be made. 29 , 34 , 35 (b) Sample preparation for validation • Frozen samples will be thawed at room temperature. • The sample will be prepared by spiking different concentrations of standard drug in 100μL of healthy subject blood, followed by separation of plasma. • The most common extraction method for protein precipitation using acetonitrile was chosen over methanol because it showed better chromatographic separation. 100 μL of acetonitrile were added to 100 μL of the plasma sample. The resulting mixture was vortexed for 5 min and centrifuged for 5 minutes at 3,000 rpm at room temperature. • The supernatant was reconstituted in 100 μL of mobile phase containing 0.1% formic acid in water and methanol and transferred to autosampler vials. Vials were placed into an autosampler (maintained at 48°C) and 10 μL of each vial will be injected. (c) Method validation. • Healthy blood samples containing different concentrations of the standard drug will be injected into the equipment. A linear regression graph was used to plot the peak area versus the concentration. The slope, intercept, and correlation coefficient will be calculated using the standard curve. (d) Chromatographic and mass spectrometer conditions • To achieve the desired chromatographic separation, peak shape, and signal intensity, method optimization will be carried out using an LC System [Shimadzu LC-MS 8045, Japan] with a Shimadzu HILIC column (150 × 2.1 mm; 3 μm) for sorafenib and a Shimadzu C8 (2 μM) column for lenvatinib with a gradient of water and acetonitrile containing 0.1% formic acid at a flow rate of 0.4 mL/min with a total run time of 5 min. The HILIC column is used for the extraction of polar compounds, such as sorafenib. The column has several advantages such as faster and efficient analysis, low-viscosity eluent usage, high cost, and high dependence on acetonitrile solvent. • An AB SCIEX 4000 Q TRAP mass spectrometer [Spectralab Scientific Inc, US] meeting the legal requirements for medical devices will be used for detection equipped with pneumatically assisted electrospray ionization (ESI) operating in the positive mode. A multiple reaction monitoring (MRM) with m/z 465→252 (sorafenib); 480.9→286.05 (sorafenib-N-oxide) and 427→370 (lenvatinib). • The MS/MS conditions were as follows: interface voltage: 4 kV; source temperature, 300°C; and oven temperature, 40°C. Analytical results will be recorded and processed using Analyst Software 1.6.3 MD [Sciex; Spectralab Scientific Inc, US]. (e) Blood sample analysis • Blood samples will be collected into EDTA test tubes by venipuncture from HCC patients satisfying the inclusion criteria during their 1st hospital visit, 7 days after drug administration, and at different time intervals (especially when an ADR is experienced). • The blood will be centrifuged at 3,000 rpm for 5 minutes to separate plasma. • From this aliquot, 10 μL of plasma will be taken mixed with 10 μL acetonitrile to precipitate plasma proteins. • The resulting mixture was vortexed for 5 min and centrifuged for 5 minutes at 3,000 rpm at room temperature. • The clear supernatant (20 μL) from each patient sample was transferred to an autosampler tube and reconstituted with 80 μL of mobile phase of 0.1% formic acid in water, and methanol will be injected into the column for analysis. Clinical study protocol During the initial visit to the Department of Medical Oncology, the investigator informs the objectives and expected benefits of the study. The volunteers are given the opportunity to decide regarding the participation in the study. Once included in the study, the blood samples are collected from the patient once the steady state concentration is achieved (2 weeks/1month). The adverse event profile, laboratory parameters, and radiological findings will be monitored during the visit. The blood sample will be analyzed and according to the reported plasma drug concentration, dose adjustments (dose increment/reduction) will be recommended. The design of the study is illustrated in Figure 1 . Figure 1. Steps involved in Therapeutic drug monitoring procedure [Created with BioRender.com ]. Sample size Based on the mean and SD, the steady-state concentration of sorafenib at dose 400 mg/d (6.1±3.9 mg/L) and at dose level 200 mg/d (4.5±4.5 mg/L) in patients with HCC who were continuously administered sorafenib orally was observed in an earlier publication, 36 with 20% allowable error and 95% confidence, the mean sample size comes to 39 for the dose 400 mg/d and 96 for the dose 200 mg/d, respectively. The minimum sample size was 96. Based on the mean and SD, steady state concentration of lenvatinib at dose 4 mg/d (0.10031+0.10123 mg/L) and at dose level 8 mg/d (0.14361+0.1587 mg/L) in patients with HCC who were continuously administered lenvatinib orally observed in the pilot study conducted in 50 samples and with 20% allowable error and 95% confidence, the sample size comes to 98 for the dose 4 mg/d, 117 for the dose 8 mg/d respectively. Total minimum sample size comes to 117. Statistical analysis • The drug plasma concentration dose will be computed as mean ± SD. • To test the statistical significant difference in the mean drug plasma concentration between 4 response of efficacy parameter, one way ANOVA followed by multiple comparison test bonferroni will be applied for skewed data or Kruskal wallis test followed bt Dunn bonferoni will be applied for skewed data. • To test the statistical significant correlation between drug plasma concentration dose and grade of ADR, Pearson’s correlation coefficient will be applied and its statistical significance will be assessed by linear reg t test. • To test the statistically significant difference in the median ADR grade between severity of disease of Child Pugh A class and Child Pugh B groups, Mann whitney U test will be applied. • Overall percentage of Objective Response Rate (ORR) and Disease control rate (DCR) will be represented in number and percentage with 95%confidence Interval. • To determine the Overall Survival (OS) and Progression free survival (PFS) of patients treated with sorafenib and lenvatinib, Kaplan Meier Analysis will be done and to compare with severity of disease in the Child Pugh A and Child Pugh B groups respectively log rank test will be applied. Study status The study is still in the recruitment phase. Sixty-seven patients who received sorafenib and eighty-eight patients who received lenvatinib have been recruited. In all subjects, blood samples were collected during the initial and follow-up visits. Expected results TDM involves combined knowledge of pharmacokinetics and pharmacodynamic activity to optimize personalized therapy. Repeated blood sampling and monitoring of adverse events are therefore necessary. This method helps to determine patient non-compliance issues and improve patient outcomes. Despite its vast applicability and impact on clinical science, TDM has not received the attention it requires. The cost involved and the tedious process of TDM limits its use in routine clinical practice. Alternate sampling techniques using dried spots that require less blood enable the care of cancer patients in rural areas. Removing the barriers to the availability, cost, and turnaround time involved in TDM will help in the wide acceptability of the method among clinicians. Conclusion Factors such as large inter-individual variability in drug absorption, genetic polymorphisms, drug interactions, and patient compliance with oral TKIs affect quality of life. Therefore, the implementation of therapeutic drug monitoring for TKIs can help reduce adverse events with maximum efficacy. The acceptance of TDM as a test in routine clinical practice can improve the survival of HCC patients with hepatocellular carcinoma. Therefore, this study has the potential to improve the clinical outcomes. Ethical approval statement The study protocol was approved by the Ethics Committee of Amrita School of Medicine (ECASM-AIMS-2021-293) on 15-06-2021 and was conducted as per principles of the Declaration of Helsinki and guidelines of the Indian Council of Medical Research. Informed consent statement Informed consent will be obtained from all subjects involved in the study in writing. Data availability No data are associated with this article. Software availability Analytical results obtained from LC-MS apparatus is recorded using using Analyst Software 1.6.3 MD [Sciex; Spectralab Scientific Inc, US] which is available at their site ( https://sciex.com/support/software-support/software-downloads ) for free download. Acknowledgments The authors would like to thank the Sophiscated Analytical Instrument Facility, MG University, Kottayam for the LC-MS equipment and research support. We would like to thank Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences and Research Centre, Kochi. References 1. Hassanpour SH, Dehghani M: Review of cancer from perspective of molecular. J Cancer Res Pract. 2017 Dec; 4 (4): 127–129. Publisher Full Text 2. Siegel RL, Miller KD, Wagle NS, et al. : Cancer statistics, 2023. CA Cancer J Clin. 2023 Jan; 73 (1): 17–48. 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Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 07 Nov 2024 ADD YOUR COMMENT Comment Author details Author details 1 Medical Oncology, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, 682041, India 2 Gastroenterology, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, 682041, India 3 Pharmaceutical Chemistry and Analysis, Amrita Vishwa Vidyapeetham, Amrita School of Pharmacy, AIMS Health Science Campus, Kochi, Kerala, 682041, India 4 Clinical Pharmacy and Toxicology, Leiden University, Leiden University Medical Center, Netherlands, 9500 2300, Netherlands Antilles 5 Sophisticated Analytical Instrument Facility (DST-SAIF), Mahatma Gandhi University, Kottayam, Kerala, 686560, India 6 Biostatistics, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, 682041, India Merin Babu Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Project Administration, Resources, Validation, Writing – Original Draft Preparation Shine Sadasivan Roles: Conceptualization, Funding Acquisition, Supervision, Writing – Review & Editing Aneesh T P Roles: Conceptualization, Formal Analysis, Methodology, Supervision, Writing – Review & Editing Teun Van Gelder Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Shiny Thomas Roles: Formal Analysis, Methodology, Validation, Writing – Review & Editing C T Aravindkumar Roles: Formal Analysis, Resources, Supervision, Writing – Review & Editing Niveditha Kartha Roles: Formal Analysis, Resources Keechilat Pavithran Roles: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This work was supported by a grant from the Indian Council of Medical Research (ICMR) Extramural Ad-hoc scheme [Project ID: 2020-9645GIA/2019/000399/PRCGIA] and sanctioned by Dr. K Pavithran. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) version 2 Revised Published: 04 Jul 2026, 13:1334 https://doi.org/10.12688/f1000research.153153.2 version 1 Published: 07 Nov 2024, 13:1334 https://doi.org/10.12688/f1000research.153153.1 Copyright © 2024 Babu M et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Babu M, Sadasivan S, T P A et al. Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :1334 ( https://doi.org/10.12688/f1000research.153153.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 07 Nov 2024 Views 0 Cite How to cite this report: Mehtani R. Reviewer Report For: Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :1334 ( https://doi.org/10.5256/f1000research.168005.r466736 ) The direct URL for this report is: https://f1000research.com/articles/13-1334/v1#referee-response-466736 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 04 May 2026 Rohit Mehtani , Amrita Hospital, Faridabad, India Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.168005.r466736 The authors have submitted a research protocol for a study analysing therapeutic drug monitoring for sorafenib and lenvatinib use in patients with HCC. I have the following comments - 1. First line systemic treatment for HCC is immunotherapy and ... Continue reading READ ALL The authors have submitted a research protocol for a study analysing therapeutic drug monitoring for sorafenib and lenvatinib use in patients with HCC. I have the following comments - 1. First line systemic treatment for HCC is immunotherapy and not sorafenib/lenvatinib. Please modify accordingly. 2. Are the clinicians blinded to the drug levels during the course of the study? 3. Were any dose modification done based on the drug levels? If yes, the same should be included in the protocol. 4. Primary outcome is not clear. It should be a measurable outcome - such as Correlation of TDM with efficacy (DCR or PFS) or correlation of TDM with safety 5. How frequently the patients will be followed up to assess side effects/response and how frequently TDM will be done needs to be elaborated. For how long each patient will be followed up needs to be clearly defined. 6. Figure 1 is not clear. Clear timeline with labelled steps should be included in the figure. 7. Please provide duration of the study. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Hepatology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Mehtani R. Reviewer Report For: Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :1334 ( https://doi.org/10.5256/f1000research.168005.r466736 ) The direct URL for this report is: https://f1000research.com/articles/13-1334/v1#referee-response-466736 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Silletta M. Reviewer Report For: Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :1334 ( https://doi.org/10.5256/f1000research.168005.r363937 ) The direct URL for this report is: https://f1000research.com/articles/13-1334/v1#referee-response-363937 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 20 Feb 2025 Marianna Silletta , Fondazione Policlinico Universitario Campus Bio- Medico, Rome, Italy Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.168005.r363937 The rationale behind the study is clear, but it is important to explain why immune checkpoint inhibitors (ICIs) are less commonly used in India. Data on overall survival and safety reports from patients treated with ICIs support the idea of ... Continue reading READ ALL The rationale behind the study is clear, but it is important to explain why immune checkpoint inhibitors (ICIs) are less commonly used in India. Data on overall survival and safety reports from patients treated with ICIs support the idea of using immunotherapy as a first-line treatment strategy. Evaluating drug concentration of TKI in second line patients who have experienced progression on ICIs or in first-line patients who are not eligible for ICIs can provide valuable insights. Some correction on pdf: Page 3: - Please refer also to phase III randomized trials and not only real world studies (REFLECT and SHARP) referring to overall survival in Lenvatinib vs sorafenib group. - Please correct the sentences According to FDA recommendations, sorafenib 400 mg (two tablets) twice daily and Lenvatinib according to body weight (8 mg once daily if weight < 60 kg; 12 mg once daily if weight ≥ 60 k g), represent the full dose but only a few patients can tolerate the total dose. Page 4: - Please add the word metabolites in the sentence: The enzymes CYP3A4 metabolize Lenvatinib and metabolites are excreted in feces - Specify what LC-MS/MS is - In primary outcome specify clinical efficacy: OS?PFS? - In secondary outcomes, point 5 add: To determine the impact of underline liver disease on overall survival (OS) and progression-free survival (PFS) - Study population The study population includes patients visiting the Medical Oncology Department of AIMS WHO (NOT AND) were diagnosed with unresectable hepatocellular carcinoma treated with sorafenib and Lenvatinib Page 5: - specify how healthy subject will be enrolled for blood sample Page 7 -Please insert a possible end-of-study date Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: medical oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Silletta M. Reviewer Report For: Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :1334 ( https://doi.org/10.5256/f1000research.168005.r363937 ) The direct URL for this report is: https://f1000research.com/articles/13-1334/v1#referee-response-363937 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 07 Nov 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 04 Jul 26 Version 1 07 Nov 24 read read Marianna Silletta , Fondazione Policlinico Universitario Campus Bio- Medico, Rome, Italy Rohit Mehtani , Amrita Hospital, Faridabad, India Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Mehtani R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 04 May 2026 | for Version 1 Rohit Mehtani , Amrita Hospital, Faridabad, India 0 Views copyright © 2026 Mehtani R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors have submitted a research protocol for a study analysing therapeutic drug monitoring for sorafenib and lenvatinib use in patients with HCC. I have the following comments - 1. First line systemic treatment for HCC is immunotherapy and not sorafenib/lenvatinib. Please modify accordingly. 2. Are the clinicians blinded to the drug levels during the course of the study? 3. Were any dose modification done based on the drug levels? If yes, the same should be included in the protocol. 4. Primary outcome is not clear. It should be a measurable outcome - such as Correlation of TDM with efficacy (DCR or PFS) or correlation of TDM with safety 5. How frequently the patients will be followed up to assess side effects/response and how frequently TDM will be done needs to be elaborated. For how long each patient will be followed up needs to be clearly defined. 6. Figure 1 is not clear. Clear timeline with labelled steps should be included in the figure. 7. Please provide duration of the study. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Hepatology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Mehtani R. Peer Review Report For: Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :1334 ( https://doi.org/10.5256/f1000research.168005.r466736) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1334/v1#referee-response-466736 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Silletta M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 20 Feb 2025 | for Version 1 Marianna Silletta , Fondazione Policlinico Universitario Campus Bio- Medico, Rome, Italy 0 Views copyright © 2025 Silletta M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The rationale behind the study is clear, but it is important to explain why immune checkpoint inhibitors (ICIs) are less commonly used in India. Data on overall survival and safety reports from patients treated with ICIs support the idea of using immunotherapy as a first-line treatment strategy. Evaluating drug concentration of TKI in second line patients who have experienced progression on ICIs or in first-line patients who are not eligible for ICIs can provide valuable insights. Some correction on pdf: Page 3: - Please refer also to phase III randomized trials and not only real world studies (REFLECT and SHARP) referring to overall survival in Lenvatinib vs sorafenib group. - Please correct the sentences According to FDA recommendations, sorafenib 400 mg (two tablets) twice daily and Lenvatinib according to body weight (8 mg once daily if weight < 60 kg; 12 mg once daily if weight ≥ 60 k g), represent the full dose but only a few patients can tolerate the total dose. Page 4: - Please add the word metabolites in the sentence: The enzymes CYP3A4 metabolize Lenvatinib and metabolites are excreted in feces - Specify what LC-MS/MS is - In primary outcome specify clinical efficacy: OS?PFS? - In secondary outcomes, point 5 add: To determine the impact of underline liver disease on overall survival (OS) and progression-free survival (PFS) - Study population The study population includes patients visiting the Medical Oncology Department of AIMS WHO (NOT AND) were diagnosed with unresectable hepatocellular carcinoma treated with sorafenib and Lenvatinib Page 5: - specify how healthy subject will be enrolled for blood sample Page 7 -Please insert a possible end-of-study date Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise medical oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Silletta M. Peer Review Report For: Therapeutic Drug Monitoring of Sorafenib and Lenvatinib in Hepatocellular Carcinoma Patients – A Key to Personalised Pharmacotherapy [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :1334 ( https://doi.org/10.5256/f1000research.168005.r363937) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1334/v1#referee-response-363937 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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