Tyrosine Kinase Inhibitor as the Treatment of Many Malignancies - Essay Example

Pharmacology al Affiliation Pharmacology Introduction Tyrosine Kinase Inhibitor (TKI) is an effective drug used in the treatment of many malignancies. According to Hartmann et al., 2009, the first drug used as TKI was Imatinib. The mechanism of reaction of the drug is such that TKI binds to the catalytic site of tyrosine kinase through competitive ATP (Adenosine Triphosphate) inhibition (Hartmann et al., 2009). It is indispensable to note that Tyrosine kinases exist as the enzymes that catalyze the movement of phosphate group to the target protein from the ATP molecules. Tyrosine kinase molecules act as the membrane surface protein for the transduction of signals to the cytoplasm. Binding of the specific ligand to the tyrosine kinases result in autophosphorylation of cytoplasmic domains and thereby activates the enzyme. Activated tyrosine kinase in turn activates the signalling pathways such as protein kinase C pathway, Scaffolding of proteins, Ras/Raf mitogen – activated protein kinase pathway, and phosphoinositol 3’ – kinase/Akt pathway (Arora and Scholar, 2005). These activated pathways alter the DNA synthesis and consequently cell growth, differentiation, and regulation. Almost all the TKI have side effects. The common side effects of TKI include anaemia, neutropenia, oedema, thrombopenia, hypothyroidism, diarrhoea, and vomiting (Hartmann et al., 2009). Consequently, TKI molecules currently remain approved for clinical trials in human. However, scientists approved TKI application for cancer treatment in dogs and cats earlier especially using TKI drugs such as Palladia (Toceranid), Gleevec (imatinid) and Kinavet (mastinib) (London, 2009). In this plan, we will investigate a variety of factors. The main concern within these toxicological studies will be to explore and evaluate the pharmacological properties of TKI. In addition, we will explore and profile drug toxicology to prevent any side effects within patients in accordance with ICH guidelines (Guideline ICHHT, 2009). After collecting the data, which contain a mixture of pharmacokinetic, pharmacodynamic and toxicology data, an approved dosage level for starting treatment within humans (FTIH) can be identified. The study should closely examine tests on toxicity in accordance with GLP standards and guidelines, using limited animals especially for model studies. Dog and rat constitutes ideal animal models with the former being used for haematology tests at a later stage. The tests that are carried out to investigate toxicology should take an approximated time frame of 6 months. Considering the drug being used is a small molecule, allometric scaling along with measurements on the weight and area under the curve should be sampled and measured Non-clinical evaluation a) Safety pharmacology tests and studies: Before conducting the safety pharmacology tests, the regulatory guidelines for testing the undesirable pharmacodynamics effects on physiological functions should be focused. This is because, in the early phase pharmacology studies, all risk factors can be found out and eliminated. TKI are found to have adverse cardiovascular effects. Therefore, when testing TKI in dogs and cats, telemetry has to be used for the continuous monitoring of systemic arterial pressure and chronotropic effects. The pharmacodynamic effects of TKI can be determined in the organs using tumour specimens. Surrogate marker can be used as an alternative approach. These tissues act as human models and TKI effect on these tissues reveals the potential effects of TKI molecules. (Kufe et al., 2003). These pharmacological screening methods enable the scientists to find out the adverse effects of TKI, and facilitate them to come up with ways on how the programme should be modified for human safety. The effect of the drug in organ function, and importantly the relevance of its potential in humans must be evaluated (Pugsley, Authier and Curtis, 2008). b) Safety studies: Animal models, in vivo and in vitro preparations can be used for the analysis. In vitro systems are used for supportive studies and in vivo studies are used to determine the dose- response relationship of the adverse effects. The safety pharmacology studies are not necessary for the treatment of end- stage cancer patients (ICH: S7A, 2000). Table 1: Invivo and Invitro test parameters: In vivo study assay In vitro study assay 1) Irwin observation test 1) hERG potassium channel test 2) Respiratory-Plethysmography (Rat) 2) ventricular wedge preparation model (Rabbits) 3) Cultured cardiac myocytes (Source: ICH: S7A, 2000) c) Acute toxicity studies The acute toxicity of the drug can be minimized by the use of targeted therapy. For the patients with chronic myeloid leukaemia, the toxicity level of the drugs has to be analysed using the guidelines for anti-cancer therapy and thereby primary a safety end point has to be achieved. Tolerance is the first safety endpoint in any clinical study. (Cortes at al., 2012) this test is rarely needed if repeat-dose studies were performed. d) Repeat dose toxicity: TKI drugs show repeated dose toxicity in rats and dogs (Mao et al., 2012). Similarly, in rats, the PF-04254644 drug was administered for a 6 – day investigative repeat-dose study (Aguirre et al., 2010). The increase in heart rate was observed from day 1 and the rate increased gradually until last day of dosage. It was observed that tachycardia occurred in the rats and it was not to the level of toxicity. Therefore, the maximum dosage level for the rodents and non- rodents should be determined. The repeated dose and toxicity levels, along with the number of animals for each group used in the study must be determined. Table 2: Analysis for Repeat-dose toxicity tests: For genotoxic drugs - One rodent is sufficient for repeated- dose toxicity test (ICH S9) The results of the repeated-dose tests for a period of 3 months are required for Phase III studies (ICH S9) In rodents, the chronic toxicity testing is performed for a 6 months duration For non-rodents, a 9 months study is performed for toxicity testing. Determination of best route of administration Dose range - a total dose of 100 microgram can be administered and maximum 5 administrations are permitted. This trial can be extended to 1species through the specific route of administration with a 1000x magnification of the clinical dose (ICH S9). A standard 2 week repeated – dose study can be performed in rodents and non-rodents with specified dose (ICH S9). (Source: ICH S4 and M3, 1998) Phases of Study a) Phase I study Phase I study is designed to investigate tolerability and safety of the drug, and identify the pharmacokinetics and pharmacodynamics of the drug. For the TKI molecules, four types of studies can be performed for the determination of dose concentration. They include a single dose study, 7-day single dose investigative study, 7- day repeat-dose toleration study, and 6–day repeat–dose investigative study. These studies can be performed in rats and dogs. The parameters such as administration route, patient’s intrinsic and extrinsic factors such as food intake, organ dysfunction, concomitant medications, absorption, distribution, metabolism, and excretion of the drug must be monitored (Fitzpatrick, 2006). Using a variety of assays, research can apply toxicokinetic studies in providing data on the pharmacokinetics of the animals that in analysis. Such data remains achievable at a variety of times during the study allowing for insight into the blood-plasma concentrations of the drug along with those that rise with time. This data will effectively measure dose range increases along with drug accumulation within the tissue. From this the upper dose toxicity levels along with the plasma concentrations of the drug can be measured and investigated which can in turn determine whether the toxic levels are reversible or not. Using the ICH guidelines, researchers can identify the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) within phase 1 studies. However, the identification of NOEL and NOAEL are retrospectively not required when verifying the use clinically of these drugs. To support phase 1 and 2 trials, study must carry out repeated single dose toxicity studies for 2 to 4 weeks within animal studies. Three months prior to testing on patients, six months worth of drug administration must be carried out on large mammal models (dog models). Table 3: Parameters to Assess in Phase I: Maximum tolerated dose Dose limiting toxicity Dosage calculation Toxicokinetic studies Repeat dose toxicity Preliminary antitumor activity of TKI Monitoring of adverse effects of TKI (Source: ICH: S9, 2009) b) Phase 2 In phase II, the therapeutic efficiency of the drug is monitored in patients. Researchers can design the study in such a way that all the parameters are compared with the baseline values. It is imperative to note that the study determines efficacy and safety of the drug, dose regimen, and dose response relationship in phase 2. Dose- response studies are continued into the phase 3 (Fitzpatrick, 2006). c) Phase 3 The pre-clinical safety pharmacology models remains improved after every result from Phase II and I. Some drugs may cross phase I and II trials with no adverse effects on humans. However, they may show liability of some adverse effects in the later stage of Phase III. The best example of such TKI is Sunitinib, which showed adverse cardiovascular effects when they are about to be permitted for the treatment of renal cell carcinoma (Pugsley, Authier and Curtis, 2008). In the Phase III studies, the dose- response relationships, use of the drug in wider population, application in different stages of diseases, and the effect of combination with another drug need focus. Phase III studies should fulfill the required instructions of US FDA for domestic as well as worldwide use of the drug. The drugs must remain checked for immunotoxicity, when the body system inhibits tyrosine kinase (Zhu et al., 2007). Pharmacologists should ensure completion of reproductive toxicology studies before marketing. However, this study is intended for prostate cancer, and therefore, Embryo-fetal toxicology tests are not required in this study. Research should perform fertility studies but not for patients with advanced stage prostate cancer. Carcinogenicity studies for the analysis of the tumorigenic potential of hte TKI molecule in animals need assessment and subsequent use in predicting the harmfulness in humans (Brock, Hastings and McGown, 2013). Bibliography Aguirre, S. A. et al. (2010).Cardiovascular effects in Rats following exposure to a Receptor Tyrosine Kinase Inhibitor. Toxicologic Pathology. 38 (3). p.416 -428. Arora, A and Scholar, E. M. (2005). Role of Tyrosine Kinase Inhibitors in Cancer Therapy. The Journal of Pharmacology and Experimental Therapeutics. 315 (3). p.971 – 979. Brock, W.J., Hastings, K.L. and McGown, K.M. (2013). Non-clinical Safety Assessment: A guide to International Pharmaceutical Regulations. Hoboken NJ: John Wiley and Sons Cortes, J. et al. (2010). Phase 2 study of Subcutaneous Omacetaxine Mepesuccinate after TKI failure in patients with Chronic – Phase CML with T3151 mutation. Blood. 120 (13). p.2573 – 80. Fitzpatrick, S. (2006). Clinical Trial Design. London: Institute of Clinical research. Hartmann, J. T. et al. (2009). Tyrosine Kinase Inhibitors – a Review on Pharmacology, Metabolism and Side effects. Current Drug Metabolism. 10 (5). p.470 -481. ICH S4 and M3. (1998). Duration of Chronic Toxicity testing in animals (Rodent and non Rodent Toxicity Testing, S4. Web. November 26, 2014. Retrieved from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S4/Step4/S4_Guideline.pdf ICH: S7A. (2000) Safety Pharmacology Studies for Human Pharmaceuticals, S7A. Web. November 26, 2014. Retrieved from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7A/Step4/S7A_Guideline.pdf ICH: S9. (2009) Non-clinical Evaluation for Anticancer Pharmaceuticals, S9. Web. November 26, 2014. Retrieved from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S9/Step4/S9_Step4_Guideline.pdf Kufe, D.W. et al. (2003). Holland- Freis Cancer Medicine Review. New York: Decker Publishing London, C. A. (2009). Tyrosine Kinase Inhibitors in Veterinary Medicine. Topics in Companion Animal Medicine. 24 (3). p.106 -112. Mao, Y. et al. (2012). Evaluation of Subchronic Toxicity of SIM010603, a Potent Inhibitor of Receptor Tyrosine Kinase, after 28-day repeated Oral Administration in SD Rats and Beagle Dogs. 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