Pharmacodynamics and Pharmacokinetics of Imatinib - Case Study Example

Case Study, Health sciences and medicine; pharmacology Executive Summary There is a lot of interest in the way imatinib, the most effective treatment therapy for for chronic myeloid leukemia works. The first interest goes on how the drug interrupts the activity of the BCR-Abl receptor tyrosine kinase fusion protein. Studies show that it does so by acting against tyrosine kinase enzyme that necessitated the signaling cascade necessary the development of cancer (Cools et al. 2003). It is also significant to know why imatinib is effective with no many side effects. Many empirical studies have given the explanation of this effectiveness (Cools et al. 2003; Killock 2014; Mitzuta et al. 2013; Stegmeier et al. 2010). The reason as to why imatinib is a selective therapy for chronic myeloid leukemia is related to the lack of adverse effects of the drug. The BCR-Abl receptor tyrosine kinase fusion protein is interrupted by imatinib through the prevention of tyrosine kinase inhibitor. The pharmacodynamics and pharmacokinetics of imatinib are effective compared to those of other drug therapies for chronic myeloid leukemia, and thus places imatinib far ahead in effectiveness in treating the disease. Imatinib is a biological treatment mainly used by people with chronic myeloid leukemia and it blocks the growth of cancer cells. As a result of imatinib drug’s action on cancer cells, doctors refer to it as a tyrosine kinase inhibitor (Marley et al. 2000). Imatinib interrupts the activity of BCR-Abl by preventing a tyrosine kinase enzyme that initiates the signaling cascade necessary for the development of cancer. This way it prevented the growth of cancer cells and as a result they die of apoptosis (Goldman 2003). Moreover, since the BCR-Abl turosine kinase enzyme is only found in cancer cells, and not in other cells, imatinib drug’s action targets cancer cells only; the reason it is referred to as a selective therapy for chronic myeloid leukemia (Stegmeier et al. 2010; Fausel 2007). There were other treatments for chronic myeloid leukemia before the development of imatinib. Such drug as interferon alpha and IFN, which was used for treating patients who were not recommended for cell transplant with or without cytarabine (Mitzuta et al. 2013). Interferon is an example of such drugs which has varying side effects on patients. Although some people wind it easy to cope with interferon, others have flue-like reactions with aching muscles and high fever (Marley et al. 2000). These side effects are likely to be more severe with older people than with young people. Imatinib is generally a well tolerated therapy for chronic myeloid leukemia with rare and mild side effects that do not lead to discontinuation. Imatinib’s side effects are frequent only in advanced phases of CML and this reflects the poor performance of many patients with chronic myeloid leukemia. A study by Peng et al. (2004) on Pharmacokinetics and Pharmacodynamics of Imatinib in a Phase I Trial with Chronic Myeloid Leukemia Patients, found confirmed the findings of Reckmann et al. (2002) that the drug is absorbed immediately it is administered orally. Among the patients under trial, Peng et al. (2004) concluded that the drug exposure was dose proportional for the dose range of 25 to 1,000 mg. Further, when they compared imatinib with AUC0-24 hours at steady-state and on day 1, there was a 1.5- to 3-fold drug accumulation after the dose is repeated once a day. Killock (2014) has found that after administration of 350 mg of imatinib at a normal state, the mean plasma trough concentration records at 570 ng/mL and above (about 1 _mol/L). This plasma concentration is more than the 50% inhibitory concentration that successfully inhibits proliferation of BCR-Abl–positive leukemic cells gotten from CML patients (Mitzuta et al. 2013). With imatinib, the relationship between the white blood cells reduction and PK parameters at normal circumstances indicate that the initial imatinib’s hematologic response depends highly on the dose administered to the CML patient and in this case, a dose higher than 400mg is needed in order to have an optimum effect on white blood cells reduction (Al Ali et al. 2002). From the above information, it is clear that the action of imatinib is therefore different and advanced as compared to the older therapies whose pharmacodynamics and pharmacokinetics are different and present chances of many side effects that in most cases lead to discontinuation of medication therapy. In the early 1990s, several studies indicated that a disease similar to CML was induced in mice when a bone marrow infected with a BCR-ABL retrovirus was transplanted (Daley et al. 1990; Heisterkamp et al., 1990). The discovery proved that BCR-ABL is the sole cause chronic myeloid leukemia. Later, Druker et al. described the compound CGP57148 as a succefful highly specific pharmacologic inhibitor of the Abl-tyrosine kinase and that does so by selectively suppressing the growth of BCR-ABL-positive cells (Al Ali et al. 2002). The compound CGP57148 was later given another name code as STI571 and later named as imatinib. Imatinib, because of its selective action on the growth of BCR-ABL-positive cells, has transformed the treatment of CML and is the first therapy developed for malignant diseases that require a specific target. Imatinib selectively suppresses the growth of BCR-ABL-positive cells because it works on the disease by exchanging genetic material in which two fusion genes; BCR-ABL on the derivative chromosome 22 and ABL-BCR on the derivative 9 are produced (Cools et al. 2003). Melo et al. 1994 supports that the expression of protein is rarely documented even though ABL-BCR mRNA is sees in almost two-thirds of CML patients. The principle applied in the process is that BCR-ABL fuses with its cognate Bcr-Abl protein (Yu et al. 2002). As a result all DNA break points happen within introns without regard to their precise location in which two types of fusion mRNA are created that have the first 13 or 14 exons of BCR combined with ABL exon 2 (e13a2 and e14a2 fusions (Deininger et al. 2000a). It has also been proven that the break in BCR rarely occurs in CML between the first and second axons leading to an e1a2 fusion mRNA (Melo et al. 1994). Other types of fusions have been reported to occur in isolated cases but are specifically frequently in acute lymphoblastic leukemia (Pane et al. 1996; Al Ali et al. 2002). This way, the variation in the BCR part of the fusion mRNA contrasts with the constant ABL part thus ensuring indicating that that it is possible for ABL to fuses with its cognate Bcr-Abl protein, and thus upholding the principle. Marley et al. (2000) proved that an approximate dose of 1 μM imatinib resulted to maximum differential effect on CML patients as also was demonstrated later by Druker et al. (2001a). It has also been demonstrated that imatinib selectively suppresses the development secondary colonies from Chronic Myeloid Leukemia Patients, just the way interferon-α does (Marley et al., 2000). The Bcr-Abl protein act on intracellular signals by activating a multitude of signaling pathways, which are potential targets for intervention, where inhibition of Bcr-Abl is not complete in itself (Druker et al. 2001a). These pathways include; Farnesyl Transferase Inhibitors in which concomitant treatment of Bcr-Abl positive cells with imatinib leads to apoptosis in case the inhibition of Bcr-Abl successful. There is also the Mitogen-Activated Protein Kinase Inhibitors in which BCR-ABL protein does not affect the proliferation of normal mononuclear cells (Yu et al. 2002). The third pathway is the Phosphatidylinositol-3 Kinase Inhibitors targetted by Bcr-Abl proten and is required by Bcr-Abl to induce leukemia in mice (Skorski et al. 1995). In affecting the intracellular signaling pathways, the Bcr-Abl induces the inhibition of individual pathways that are sufficient to prevent the shuting down of the entire system (Sexl et al. 2000; Li et al. 2001). 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