INTRODUCTION:

One of the most important medical discoveries in recent decades seems to have been chemotherapy for cancer. Unfortunately, because of the narrow therapeutic index of the drugs used in this treatment, the outcomes are frequently only temporary and unreliable. In contrast, more recent tailored medicines focus on chemicals and signalling pathways that are unique to cancer, causing fewer non-specific side effects. The fact that tyrosine kinases are involved in the modification of growth factor signalling makes them a particularly crucial target¹. An enzyme called protein kinase phosphorylates other proteins. The end-phosphate unit of ATP is directly joined to threonine, serine, or tyrosine amino acids during kinase phosphorylation^2,3. It is widely accepted that kinase dysregulation increases oncogenic potential and dysfunction can be brought on by point mutations, overexpression, fusion, translocation, and dysregulation of upstream pathways, among many other methods^4,5,6,7. TCKIs signalling pathways are intricate, including a growing number of biochemical processes and molecular regulators in intricate signalling systems.

TCKI has an effect on a few intermediaries, including phosphoinositide 3-kinase, mitogen-activated protein kinases (MAPK) and calcium signalling. RTKs primarily activate the Pi3K/AKT/mTOR, phospholipase C (PLC) or CaMK-PKC pathways, RAS/MAPK, and Janus kinase (JAK) which are downstream effectors of various mechanisms during cancer pathogenesis (Figure.1)⁸. In addition to afatinib, zanubrutinib, osimertinib, neratinib, ibrutinib, acalabrutinib and dacomitinib, which have all received FDA approval, there are other TCKIs that are under clinical investigation. A number of articles describing the design, validation, and application of bioanalytical methods for tyrosine KIs have been published as a result of the growing need for bioanalytical techniques to qualitatively and quantitatively study such substances^9,
10,11.

For example, the signalling network of the epidermal growth factor receptor includes 211 biological reactions and 322 signalling compounds¹². The EGFR family encompasses four types of growth factor receptors, such as EGFR (ErbB1- EGFR/HER1R, ErbB2 (HER-2 neu in rodents), ErbB3 (HER-3) and ErbB4 (HER-4). Many human tumours have mutations that result in continuous activation, amplification, and overexpression of EGFR proteins, including tumours of the mammary glands, ovaries, kidneys, and lung. These alterations are a factor in tumour metastasis. EGFR overexpression or excess activation is common in Non-small cell lung cancer (NSCLC), which is the foremost reason for cancer-associated deaths in the Western world^13,14,15,16 EGFR mutations are found in about 10% of all patients, but this rate can reach 40% in Asians, non-smokers, and patients with adenocarcinoma histology. The most common EGFR mutations are deletions at exon 19 and point mutations at exon 21 (L858R). The existence of these alterations suggests susceptibility to EGFR TKIs like gefitinib, erlotinib, and afatinib. Gefitinib and Erlotinib (first generation), second generation (Afatinib, dacomitinib, neratinib), and third generation (AZD9291 (osimertinib), CO-1686 (rociletinib), HM61713, EGF816X, ASP8273) TKIs) TKIs are now a prominent therapeutic option widely chosen in daily routine practice because of the considerable survival benefits they have produced^17,18.

As numerous attempts are made to investigate more Tyrosine KI candidates, For the development of this innovative class of medications, bioanalysis is increasingly important, particularly for the pharmacokinetic and pharmacodynamic evaluation of those chemicals. Because of this particular cause, therapeutic drug monitoring (TDM) of TKIs and TKIs is frequently utilised for clinical outcomes, highlighting the significance of TCKIs bioanalysis in a regular clinical environment¹⁹.

In light of the quick rise and development of TCKIs, it is crucial to have this review describe the mechanism of TCKIs, current bioanalytical assays of tyrosine KIs, and their metabolites in order to offer a glimpse into the most recent bioanalytical patterns in this oncologic research area and to provide preliminary data that could be helpful to developing bioanalytical methods for approaching potential molecules in the TCKIs group.

Figure 1: Mechanism of Tyrosine kinase pathway⁸

Analytical and Bioanalytical Techniques:

Pharmacokinetic knowledge is necessary for the discovery and characterization of novel therapeutics and drug candidates, including TCKIs. To determine a drug's pharmacokinetic properties, reliable and precise bioanalytical procedures to measure the amount of the drug and its by-products in human biological fluids are needed. In many cases, preliminary research on small rodents (mice and rats) is the first step before moving on to clinical treatments using human samples. Samples generated from blood (i.e., serum and plasma) are used for the majority of bioanalytical procedures because they provide the fundamental information required for study and the assessment of treatment outcomes as well as the efficacy of drugs²⁰. Plasma is the biological resource most frequently used in the clinical context for drug assessment for TCKIs. The development of quick, accurate, and highly sensitive bio-analytical tests is required to accomplish this goal. Only a few HPTLC, High Performance Liquid Chromatography –UV detector, and LC-MS/MS procedures have been published.

The sample techniques which are typically used in bioanalysis include:

MS DETECTION:

The fraction of a molecule that has become an ion or has subsequently produced smaller fragments is detected by a mass spectrometer (MS). In TCKI Bioanalytical assays, tandem mass spectrometry (MS/MS) is frequently utilised. When compared to other techniques, MS has some advantages, such as its outstanding specificity and responsiveness Also, it has a connection to both gas-phase (GC-MS) separation and liquid-phase (LC-MS) and. Liquid chromatography in conjunction with mass spectrometry is currently the primary method used to analyse small-molecule tyrosinase inhibitors (LC-MS)^21,22,23,24 .

As these advances in technology, it has lately been used to analyse metabolites and other chemicals in biological fluids including urine and plasma. The phrase "MS/MS" refers to the mass spectrometry investigation, which involves subjecting mass-selected ions to a second spectrometric measurement. Thus, for MS/MS, at least two phases of m/z analysis are required. There are various MS/MS varieties that are offered commercially. Although only these MS/MS instruments have been used in TCKI's bioanalysis to date only quadrupole TOF (Q-TOF, triple quadrupole (QqQ), and quadrupole-orbitrap (Q-Orbitrap) will be taken into consideration in this study ^25,26,27.

In comparison to light spectroscopic detection techniques, bioanalytical studies using MS detectors require a rather expensive detector, and such equipment isn't always accessible in every diagnostic laboratory or hospital. So, instead of using MS/MS in such a case, a different detector like a UV-Vis/diode array detector (DAD) might prove more appropriate. The selectivity of DAD is reported to be at least one or two orders of magnitude less sensitive than low-resolution MS ^{28, 29}. Higher sample volumes with greater analyte quantities (ca. 100–500 µL) may be an alternative to solve this issue³⁰. According to Croitoru et al., sensitivity below 1 ng/ml can be attained by Diode Array Detector in ibrutinib quantification with a minimum of 1 ml of human plasma samples prepared by the liquid-liquid Extraction technique. Consequently, the necessity of 1 ml of human plasma sample will be a difficulty in preclinical research using small rodents (rats). This is likely the cause of the reason that plasma is used for Tyrosine KIs bioanalysis using an ultraviolet-diode array detector (Table1) ³¹.

For example, Wen Jiang et al employed a method and then compared it with other published techniques. They effectively built and optimized a method employing UPLC-MS/MS for the detection of 9 tyrosine KIs in plasma. They employed a Hypersil GOLD VANQUISH C18 column with a solvent system of ACN and 0.1% formic acid in water. The following procedure for gradient elution was executed: The mobile phase B was initially set to 85 percent for 0.5 minutes, after which the proportion was gradually reduced to 5% at 0.5-2 minutes and kept for 4 minutes, the mobile phase B was then quickly restored to 85%, and in the final minute, equilibrium was maintained.

They also stated that the analysis took 8 minutes to complete and that the flow rate of mobile phase was 0.3 ml/min with a 5 L injection volume. The drugs like cabozantinib, apatinib, Lenvatinib, sorafenib, gefitinib, regorafenib, and anlotinib all showed good linearity over the 0.1–10 ng/ml range, and tivantinib and galunisertib showed linearity over the entire 1-100 ng/ml range. Linear correlation coefficients for all standard curves are less than 0.9966. Finally, the study found that the limits of quantitation at 0.003 to 0.11 ng/ml and detection (LOD) at 0.01-0.37 ng/ml. This method's selectivity, accuracy, and matrix effect (ME) range of 90.48–107.77% were all assessed as adequate ³².

Table 1: Detailed information on bioanalysis of TKIs are listed above ³¹

Drugs	Another drug/ metabolite	Medium	Column	Mobile-phase	Elution	Range (ng/ mL)	Detector
Naquotinib³³	Not any	Rat Plasma	Ethylene Bridged Hybrid-C18	A:5mM Ammonium formate buffer B: ACN-0.1% F	Gradient	5 – 491	QqQ
Neratinib ³⁴	No	Human liver microsomes	Eclipse Plus C18	Acetonitrile-10 mM and NH4COOH (45:55 v/v)	Isocratic mode	5 – 500	QqQ
Olmutinib ³⁵	No	Rat plasma	Eclipse Plus RRHD C18	A: 0.1% Formic acid in water B: Acetonitrile	Gradient mode	1 – 500	QqQ
Pelitinib ³⁶	No	Human plasma	Ethylene Bridged Hybrid-C18	A: 0.1% Formic acid B: ACN C: water, D: CH3OH	Gradient mode	1 – 200	QqQ
Spebrutinib ³⁷	No	Human plasma	Eclipse C18	10mM Ammonium formate and ACN (60:40 v/v)	Isocratic mode	5 – 500	QqQ

Table 2: Determination of Tyrosine KIs by using HPLC Method

Drugs	Material	Column	Mobile phase	Detection (UV)nm	Ref
Dasatinib	Dosage form	C18	CH3OH and ACN mixed in the ratio of 50:50 v/v	323	40
Lapatinib	Tablet dosage form	ODS C18 RP	ACN and H₂O (50:50 v/v)	232	41
Sorafinib	Tablet	Phenomen ex C18	ACN and water in the ratio of 82. 5: 17.5 v/v.	265	42
Imatinib	Pharmaceutical dosage form	Phenomenex (4.6mm X150 mm) 5µ	Orthophosphori-c (pH 2.5): CH3OH (50:50)	263	43
Nintedanib	Drug	Silica gel-60 F-254	CHCl3:CH3OH in the ratio 7:3 v/v.	386	44
Sunitinib	Human plasma	Cyanopropyl	Ammonium acetate buffer: ACN(55:45, v/v)	431	45

Table 3: Validation parameters by using HPLC

Parameters	Gefitinib	Icotinib	Erlotinib	Crizotinib	Osimertinib	Afatinib
Linearity range (ng per spot)	100–1000	50.0–4000.0	50.0–4000.	10.0–1000.0	10.0–1000.0	5.0–400.0
Precision (%R.S.D.)	6.31	1.81	1.87	7.27	7.27	5.76
Inter-day (n = 6)	10.59	-0.40	-5.64	7.71	11.38	8.92
intra-day (n = 6)	13.04	−1.68	−3.25	7.71	12.35	10.33

HPLC:

In order to measure tyrosine KIs, such as imatinib, nilotinib, and dasatinib in body fluid, analytical techniques based on HPLC-UV were published.^38,39

Yanping Liu et al., quantitatively analysed 6 TKIs (gefitinib, osimertinib, icotinib, erlotinib, afatinib and crizotinib) by using HPLC.^40-⁴⁶

HPTLC:

A recent study developed and validated a HPTLC technique for detection of imatinib mesylate that is straightforward, accurate, and resilience. The protein kinase inhibitor efficiently suppresses the Abelson tyrosine kinase. Protein Tyrosine kinase has a ability to transfers phosphate molecule from Adenosine Tri Phosphate to tyrosine residues in cytoplasmic protein substrates. PTKs have a vital function in modulating signal transduction pathways⁴⁷. Because of its advantages, HPTLC is now becoming a standard analytical method^48,49.

In contrast to HPLC, HPTLC enables the simultaneous testing of multiple samples using a minimal amount of mobile phase, which shortens analysis times and lowers per-analysis costs. In the literature, various methods for analysing imatinib mesylate are available, such as High Performance Liquid Chromatography and LC-MS-MS. However, there is no existing HPTLC approach to assessing imatinib mesylate in bulk and dosage form^50,
51,52.

Furthermore, none of them is a method for indicating stability. They sampled the spotted with a Camag microliter syringe on precoated Plate 60F-254 using a Camag Linomat IV, according to previously published article. A continuous application speed of 100nl/s was used, with an 8 mm space between two bands. The mobile system was mixture of chloroform and methanol (6:4 v/v). The chamber was optimised, and the mobile phase system was run for 30 minutes at room temperature. The chromatogram run length was around 70 mm, with absorbance mode set to 276nm (Table.4)⁵³.

Table 4: Overall validation parameters of imatinib mesylate

Parameter	Data
Linearity range (ng/spot)	between 100–1000
Correlation coefficient	0.9966 ± 0.0013
LOD (ng/spot)	10
LOQ (ng per spot)	30
Precision (%R.S. D)
Repeatability of application (n = 6)	0.35
Repeatability of measurement (n = 6)	0.16
Interday (n = 6)	0.74
Intraday (n = 6)	0.48
Robustness	Robust
Specificity	Specific

DISCUSSION AND CONCLUSION:

In general, bioanalysis may contain as few manual processes as possible and simple, high-throughput experiments. The clinical relevance of bioanalysis of multianalytes in oncology is frequently noted because many cancer patients take numerous drugs. Gradient elution is frequently utilised in these situations, with more than 10 analytes, to get a trustworthy separation in the least amount of run time⁵⁴.

The bioanalysis of TCKIs is significant for the study of drugs and cancer. The tests created in recent years offer a better understanding of PK/PD characteristics, metabolism, drug-drug interactions, and drug-food interactions. These assays can increase efficacy and decrease the toxicity of tyrosine KIs through TDM in conjunction with research on the therapeutic target level and clinical exposure effect. The researchers have an interest in learning more about this group of anti-cancer drugs. This article's information cuts down on the time and amount invested in developing analytical methods for analysing tyrosine kinase inhibitors from the very beginning. This knowledge will be useful for any future studies.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGEMENT:

The authors are thankful to the principal and management of Acharya and BM Reddy College of Pharmacy, Bengaluru for providing facilities including plagiarism, interest, books etc.

FUNDING:

This work did not receive any specific grant from funding agencies in the public, commercial, or not -for-profit sectors.

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Received on 25.08.2023 Modified on 21.12.2023

Research J. Pharm. and Tech 2024; 17(6):2949-2954.

DOI: 10.52711/0974-360X.2024.00461