S. NO

Details

Multi Kinase inhibitors

Immune check point inhibitors

1

List of drugs

Sorafenib, Lenvatinib, Cabozatinib, Infigratinib phosphate, Futibatinib Pegaptanib, Regorofinib.

Atezolizumab, Bevacizumab, Durvalumab, Pembrolizumab, Ramucirumab, Tremelimumab, Ipilimumab, Nivolumab.

2

Drug targets/drug profile

Protein kinases are intracellular enzymes that regulate cell growth & proliferation as well as triggering & regulation of immune responses. Protein kinase play a crucial role in cancer by regulating signaling pathways that control cell growth survival & proliferation. Targeting these kinases with specific inhibitors can disrupt these pathways. Offering potential therapeutic avenues to inhibit cancer progression & promote cell death in malignant cells. Protein kinases are enzymes that catalyze the transfer of phosphate groups from ATP to specific amino acids on target proteins, there by regulating their activity. Kinases associated with liver cancer:

1. Epidermal growth factor receptor (EGFR): overexpression or activation EGFR is observed in a subject of HCC cases, promoting cell proliferation and survival

2. Fibroblast growth factor receptor (FGFR): FGFR signaling is implicated in HCC progression, promoting cell growth, angiogenesis, and metastasis.

3. Vascular endothelial growth factor receptor (VEGFR): activation of VEGFR promotes angiogenesis in HCC, facilitating tumor growth and metastasis.

4. Hepatocyte growth factor receptor (c-Met): Dysregulation of c-Met signaling contributes to HCC development and progression, promoting cell proliferation, migration, & invasion.

5. Pl3K/AKT/m TOR pathway: Kinases within this pathway, including phosphatidylinositol-3 kinase (Pl3K), AKT, & mammalian target of rapamycin [m TOR], are frequently dysregulated in HCC, promoting cell survival, proliferation, & metabolism.

6. MAPK pathway: components of the mitogen-activated protein kinase (MAPK) pathway, such as Ras, Raf, MEK, & ERK, are often activated in HCC, driving cell proliferation, survival, & metastasis.

7. Checkpoint kinases: checkpoint kinases like CHK1 & CHK2 are involved in cell cycle regulation & DNA damage response. Dysregulation of these kinases can contribute to genomic instability and tumor development in HCC.

8. CDKs: Cyclin-dependent kinases (CDKs), such as CDK4 & CDK6, regulate cell cycle progression & are frequently dysregulated in HCC, promoting uncontrolled cell proliferation.

Immunity plays a significant role in liver cancer, particularly in the context of Hepatitis B & Hepatitis C virus infections, which are major risk factors for development of liver cancer. Immune checkpoint pathways such as the PD-1, PD-L1 axis, play a crucial role in regulating the immune response in liver cancer. Overexpression of PD-L1 on tumor cells can inhibit T-cell function, allowing cancer cells to evade immune destruction. Immune check point inhibitors are drugs that enhances the immune system’s ability to recognize and attack cancer cells. Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option for liver cancer, particularly hepatocellular carcinoma (HCC). ICIs work by blocking inhibitory checkpoints on T cells, such as PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), thereby enhancing the immune response against cancer cells. Several clinical trials have investigated the efficacy and safety of ICIs in patients with advanced HCC. Drugs like nivolumab, pembrolizumab, and atezolizumab have shown promising results in some patients. Pembrolizumab was the first ICI to receive FDA approval for the treatment of patients with HCC who have previously been treated with sorafenib, based on the results of the KEYNOTE-224 trial. ICIs are often studied in combination with other systemic therapies, such as tyrosine kinase inhibitors (e.g., sorafenib) or anti-angiogenic agents, to enhance their efficacy. Biomarkers like PD-L1 expression and tumor mutational burden (TMB) are being investigated to predict response to ICIs in HCC. However, there is currently no consensus on their utility in guiding treatment decisions. While ICIs have shown efficacy in some patients, they can also lead to immune-related adverse events (irAEs) that affect various organs. Close monitoring and management of these side effects are essential during treatment. Ongoing research is focused on identifying predictive biomarkers, optimizing treatment strategies (including combination therapies), and exploring the role of ICIs in earlier stages of HCC. Overall, immune checkpoint inhibitors represent an important therapeutic avenue in the management of liver cancer, offering new hope for patients with advanced disease.

3

Mechanism of actions

Sorafenib,

Lenvatinib,

Cabozatinib,

infigrinatib Phosphate,

futibatinib,

Pemigatinib,

regorafenib.

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Targets multiple kinases

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Inhibition of kinases EGFR,

FGFR,

VEGFR,

CDKs,

RAF,

PDGFR,

KIT,

RAT

↓

Downstream effects Anti-angiogenesis,

cell growth inhibition,

apoptosis induction

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Clinical effects anticancer activity, tumor regression.

Atezolizumab,

bevacizumab,

durvalumab,

pembrolizumab,

ramucirumab,

tremelimuma,

ipilimumab,

nivolumab.

↓

T-cell activation. These inhibitors primarily target T- cells, a type of white blood cell involved in the immune response.

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PD-L/PD-L1 pathway:

Most immune checkpoint inhibitors block the interaction between programmed cell death protein 1 on T-cells and programmed death ligand-1 on cancer cells or other immune cells.

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CTLA-4 Pathway:

Some inhibitors target cytotoxic T-lymphocyte associated protein 4, which regulates T-cell activation.

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Inhibition of checkpoint proteins Blockade of PD-1 / PD-L1 pathway and CTLA-4 pathway

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Enhanced antitumor immunity.

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Clinical effects – anti cancer activity,

tumor regression

4

Polymers

Polymers (MKls)- PLGA (poly D, L lactide co glycolide), PCL (poly e caprolactone), PLA (poly lactic acid) are the polymers which are mostly used in the formulation of tyrosine kinase inhibitors.

Hydrogels are complex structures of cross-linked polymeric chain, which are used in formulation to control the release rate of drug.

Oils such as captex 300 are used in formulation of low soluble drugs.

Surfactants such as kolliphor RH 40, transcutol HP are used.

HPMC K4M is used as precipitation inhibitor.

Polymers (lCls)- No polymers are used in formulation of immune check point inhibitor drugs (as they control and expands the time of drug release).

Most of the drugs which of the immune check point inhibitors are administered through lV infusion for immediate release.

5

Therapeutic activity (Pharmacokinetics)

Multi-kinase inhibitors are typically administered orally and undergo absorption in the gastrointestinal tract.

Factors such as solubility, formulation, and food intake can affect their absorption rates.

In patients with liver cancer, alterations in gastrointestinal function due to liver dysfunction or other comorbidities may influence drug absorption.

Distribution: Once absorbed, multi-kinase inhibitors are distributed throughout the body, including to the liver tumor tissue. However, distribution may be influenced by factors such as protein binding, tissue perfusion, and the presence of efflux transporters.

In liver cancer patients, altered hepatic blood flow and potential liver metastases may affect drug distribution to the liver.

Metabolism: Multi-kinase inhibitors undergo hepatic metabolism primarily via cytochrome P450 enzymes, particularly CYP3A4. Liver dysfunction associated with liver cancer can affect drug metabolism, leading to altered plasma concentrations and potentially increased risk of adverse effects. Additionally, drug interactions with other medications metabolized by the same enzymes should be considered.

Excretion: Multikinase inhibitors and their metabolites are primarily eliminated through hepatic and renal routes. Liver dysfunction can impair drug clearance, leading to prolonged drug exposure and increased risk of toxicity. Renal impairment may also affect drug excretion, although it is less common with most multi-kinase inhibitors.

Absorption: ICIs are typically administered intravenously, leading to rapid and complete absorption into the bloodstream.

Distribution: They distribute widely throughout the body, reaching tumor sites as well as peripheral tissues. However, the distribution may be limited by factors such as protein binding and tissue penetration.

Metabolism: ICIs, such as monoclonal antibodies targeting PD-1, PD-L1, or CTLA-4, are primarily metabolized by proteolytic degradation or catabolism, like endogenous immunoglobulins .

Elimination: The elimination half-life of ICIs varies but can be relatively long, ranging from weeks to months. They are eliminated via proteolysis and clearance by the reticuloendothelial system.

Factors affecting PK: Factors such as renal or hepatic impairment, patient’s immune status, and concomitant medications may influence the pharmacokinetics of ICIs.

Name of the drug

BCS classification

Mechanism of action

Half-life

Bioavail- ability

Therapeutic efficacy / Overall response rate

Sorafe nib

Class 2

Multikinase inhibitors

20-48 hours

38-49%

56.8%

Lenvat inib

Class 2

Multikinase inhibitors

28 hours

85%

81%

Caboz atinib

Class 2

Multikinase inhibitors

99 hours

25-77%

32%

Infigrat inib phosphate

Class 4

Multikinase inhibitors

33.5 hours

1.5-51%

-

Futibat inib

Class 2

Multikinase inhibitors

2.3 hours

11.2%

13.7%

Pemig atinib

Class 2

Multikinase inhibitors

5 hours

14-41%

36%

Regora fenib

Class 2

Multikinase inhibitors

20-30 hours

69-83%

9%

Atezo lizumab

-

Immune check point inhibitors

27 days

Subcuta- neous 30%

24%

Bevaci zumab

-

Immune check point inhibitors

4.8 days

Subcuta- neous 1%

73.2%

Durval umab

-

Immune check point inhibitors

18 days

Intravenous administration

42.9%

Pembro lizumab

-

Immune check point inhibitors

26 days

Intravenous administration

20-50%

Ramuci rumab

-

Immune check point inhibitors

10 days

Intravenous administration

9.1%

Tremeli mumab

-

Immune check point inhibitors

22 days

Intravenous administration

25%

Ipilimu mab

-

Immune check point inhibitors

14.7 days

Intravenous administration

28%

Nivolu- mab

-

Immune check point inhibitors

20 days

Intravenous administration

82.9%