A Molecular Mechanics Model for Imatinib and Imatinib

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Table of Contents

Introduction
Pharmacodynamics implications
Pharmacokinetic implications
Alternative treatment
Conclusions
Reference List

Introduction

Chronic myelogenous leukemia is a hematopoietic disorder that affects the clone. It is identified by the displacement of chromosomes (9 and 22) and it ends up in the creation of novel fusion genetic code of Philadelphia translocation. The constitutive activity of tyrosine kinase highly contributes in the pathogenesis process of the disease. If a timely bone marrow transplant is not carried out on the patient, the patient can survive for approximately 3 to 5years (Daub, Specht & Ullrich 2004). High percentages of deaths are experienced from the time of the disease progresses to its advanced stage. Within the progress and advanced stage duration, a rapid proliferation and a transformation of lymphoid blasts from blasts process takes place. The chance of the patient surviving at the terminal blast stage is low. Chronic myelogenous leukemia can be treated by a therapy known as Imatinib. It is a tyrosine kinase inhibitor and is used in clinics. Imatinib selectively inhibits CML cells proliferation. Imatinib mesylate is a therapy adopted to care and treat chronic myelogenous leukemia. Imatinib is heterogeneous in patients who harbor BCR-ABL mutations (Daub, Specht & Ullrich 2004).

Pharmacodynamics implications

The introduction of Imatinib mesylate therapy has shown a great improvement on CML treatment. The advance made on the treatment is a 2-phenylaminopyrimide and selective inhibitor of BCR-ABL. Imatinib plays a central role in patients with CML. It is also the required standard for managing the disease. Long lasting, continuous extensions and developments are produced by Imatinib and they increase the patient’s chances of surviving. Although Imatinib shows high rate of its initial response, about 10% of the patients who are in their early phase of CML display primary cytogenic resistance (Aleksandrov & Simonson 2010). The treatment of CML to such patients may also fail. Imatinib mesylate therapy fails in patient due to biological factors like BCR-ABL mutations and other variation in genes. Features in clinics also contribute to the failure of Imatinib mesylate therapy. The features include the current status of the disease or high score of sokal risk (Buschbeck 2006).

IM Plasma trough levels variations also affects the molecular and cytogenetic responses in CML patients. Patients The Imatinib trough plasma concentration has an interrelationship with clinical response in various tumors that can be identified. The level of concentration of the mean trough plasma of Imatinib is higher in patients with a complete cytogenic response than those patients who lack CCR at an equal mean of daily Imatinib dose (Buschbeck 2006). The estimation of cumulative CCR rate and MMR varies among the qualities of Imatinib trough level. Imatinib trough plasma concentration can be achieved and maintained suppose a patient responds positively towards the therapy. High concentration of Imatinib are related to great risk of fluid retention, rash, anemia, low risk of fatigue, pain in the abdomen and pain in the joints. Some of the effects are an outcome of speed of therapy response. Toxicity remains are predicted by Imatinib plasma concentration. A dependable plasma concentration can be carried through after approximately a one week therapy. There is a high difference of Imatinib plasma concentration among patients. A French study revealed that large interpatient level differences in patients with CML receiving at 400mg/day IM trough concentrations ranged from 181 to 2947ng/ml (Aleksandrov & Simonson 2010).

Pharmacokinetic implications

There are a number of differences that have been identified in Imatinib plasma concentration. There is poor compliance due to need of prolonged long life therapy. Approximately 95% of patients who adhere to the therapy have life threatening diseases. Approximately 40% of patients were compliant to the therapy. There are some demographic factors that showed mild effect on exposure of Imatinib. Such factors include sex, age and body weight. Imatinib is metabolized by a protein p450 via CYP3A4 isoform. The drug to drug interference is as a result of the patient using other drugs that are cytochrome enzyme inhibitors. Also the level of Imatinib can be altered by disease affecting gastrointestinal tract because of improper absorption and plasma protein binding of IM differences (Sacha 2014).

It is easy to evaluate and assess the concentration of Imatinib trough plasma. The blood concentrations of trough samples are collected at a steady state before the morning dose. Here, a specific liquid known as either chromatography –mass spectrometry or high performance liquid chromatography, in collaboration with protocols of tandem mass spectrometry are used to determine the trough sample concentration. The liquids have to be well validated. The quantity of Imatinib can be determined by diode array detection, HPLC and ultraviolet. The methods need serious validations according the patient current prescriptions of food and drug. Imatinib has no clear definition of therapeutic concentration window. Good cytogenic and molecular responses achievement are significantly connected with concentrations of plasma Imatinib concentration which are more than 1002 ng/ml and Imatinib more than 1009 ng/ml. The concentration of plasma trough above 1000 n/ml mean population is important for superior rates of CCR and MMR achievement (Liu et al. 2005).

Alternative treatment

Measuring therapeutic drugs is very critical in various clinical situations. In cases where patients fail to respond to treatment the clinician can get assistance by measuring the trough plasma Imatinib concentration of which it will make him make decisions on the patients’ dosage. If a patient experiences severe adverse reactions, reduction of dose may be of great assistance. Once a medical expert suspects drug to drug interference which might be caused by a drug that has unknown interaction with Imatinib or monitoring indicates low concentration of Imatinib, then he/she should increase Imatinib dose and also stop the suspected drug and replace it with a safer one. A repeat should be carried out on a patient by a clinician to maintain therapeutic Imatinib concentration and it should be done after invention. If a clinician notices a poor level caused by suboptimal response, it will be essential for him/her to check drug compliance. Clinical situation should determine the need for treatment decision on interference, dose reduction and change on the therapy although plasma concentration measurement might be of great assistant to a clinician when handling complications (Werner et al. 2011).

Conclusions

Trough plasma concentration measurements provide other tools for handling patients who are under Imatinib medication. Such cases occur when a patient develops unusual toxicity. Evidence to proof the effect of alternating the strategies of therapy on trough plasma concentration ground has not yet been established. This means that changing therapeutic strategies is not an alternative therapeutic tool. There are multiple factors including exposure of plasma that are effective to response. The therapeutic baseline of 1000 ng/ml is the required populations mean value that is linked with clinical response (Daub, Specht & Ullrich 2004). There is inadequate data on the importance of longitudinal measurement of concentration of trough plasma. The frequency of P-loop and T3151 BCR-ABL mutations are more in advanced phase specifically in blast crisis CML patients. The cause of the condition is an outcome of the occurrence of chromosomal changes frequently monitored at the relapse time at the advanced phase of CML.

The number of cells at mutation risk and the rate of mutation depend on the likelihood of Imatinib resistance mutation occurrence. Mutations discoveries should be solved by alternative therapies that are adopted in majority cases. Decisions should be made in accordance with the clinical situation whenever a plasma concentration is measured and interpreted. There is hope for patients who experience low level of plasma because a clinical trial that monitors the impact of increase in dose is being developed. Imatinib is a preferred treatment of a growing tumor on the walls of intestines i.e. gastrointestinal stromal tumors. Imatinib can also be a treatment to dermatofibrosarcoma protuberant which is a tumor that develops under the skin’s top layer. Imatinib works as a blockage to the abnormal protein action that encourages the cells of cancer to spread. It is vital for a clinician to be aware of whether Imatinib escalation dose is partially or totally resistant, so that he/she comes up with decisions that overcome the resistance. The decisions might improve the final results of Imatinib. It is necessary for a clinician to identify the early characteristics of BCR-ABL mutations in Imatinib resistant CML patients so as to develop the required therapeutic strategy (Daub, Specht & Ullrich 2004).

Reference List

Aleksandrov, A & Simonson, T 2010, “A molecular mechanics model for imatinib and imatinib:kinase binding”, Journal of Computational Chemistry, vol. 31, no. 7, pp.1550-1560.

Buschbeck, M 2006, “Strategies to overcome resistance to targeted protein kinase inhibitors in the treatment of cancer. Drugs in R&D [Drugs R D], vol. 7, no.2, pp. 73-86.

Daub, H, Specht, K & Ullrich, A 2004, “Strategies to overcome resistance to targeted protein kinase inhibitors”, Nature Reviews Drug Discovery, vol.3, no.12, pp.1001-1010.

Liu, P, Li, J, Han, Z, Lu, H, Wang, Y, Xu, & Peng, Z 2005, “Elevated plasma levels of vascular endothelial growth factor is associated with marked splenomegaly in chronic myeloid leukemia”, Leukemia & Lymphoma, vol. 46, no.12, pp.1761-1764.

Sacha, T 2014, “Imatinib in Chronic Myeloid Leukemia: an Overview”, Mediterranean Journal of Hematology & Infectious Diseases, vol. 6, no. 1, pp.1-9.

Werner, B, Lutz, D, Brümmendorf, TH, Traulsen, A, Balabanov, S 2011, “Dynamics of Resistance Development to Imatinib under Increasing Selection Pressure: A Combination of Mathematical Models and In Vitro Data”, PLoS ONE, vol. 6, no.12, pp.1-8.

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