Medication Paper Rough Draft

Answer

  Abstract

Given the growing prevalence of cancer and its related disorders, it is important to have a deep understanding of medications which have been proved to have positive impact in reducing such diseases. This paper analyses ponatinib as one of the medicines used to treat cancer diseases such as chronic myelold leukemia and acute Lymphonoblastic leukemia. The paper describes indications, uses, dosages, side effects, pharmacology, and interaction of ponatinib. Known as a major treatment medication for chronic myelold leukemia and acute Lymphonoblastic leukemia this essay also describes how it reduces the symptoms of such diseases and restoring life to normal. The paper concludes by providing certain contraindication of the drug which patients and doctors should be aware of before its prescription.

Introduction

Cancer is among the leading causes of death which accounted for approximately 9.8 million deaths in the year 2018. This statistic is worrying hence there is a need of pharmacological interventions to prevent cancer. One of the drugs that has been used to treat certain types of cancer is ponatinib. Ponatinib is a third-generation tyrosine 9TKIs) kinase inhibitor that is very active on patients with chronic myeloid leukemia (CML) and patients who are resistant to multiple tyrosine kinase inhibitor (TKIs). The drug is used to treat chronic myelold leukemia and acute Lymphonoblastic leukemia. The reason behind the selection of this drug is the prevalence and the stigma of cancer, specifically chronic myelogenous leukemia. This is a disorder which is characterized by augmented proliferations of granulocytic cell line without loss of their capacity to differentiate. It accounts for 20% of all leukemias affecting adults. In the current society, the stigma of cancer related disease has caused deaths which could have been prevented. According to the study conducted by Gover-Proaktor et al. (2015), most patients die from cancer simply because of the stigma. It is in this context that it is important to research some of the important drugs that have been used to prevent cancer so that the society can actually note that there are some pharmacological interventions to prevent cancer related diseases. Additionally, Ponatinib is a third-generation TKI that counteracts emergence of resistant clones in preclinical studies and has showed substantial medical advantage in patients with refractory CML (Nazha et al., 2015). This is another interesting reason why ponatinib has been chosen for this study, specifically to understand its components and pharmacological mechanism. It is in this context that this paper discusses ponatinib, its mode of actions, dose and uses, side effects, interactions, contraindication, and its role in prevention of Chronic myelogenous leukemia.

Drug and Medication Information

Physical and Chemical Composition

The Pubchem CID for ponatinib ID is 24826799, the InChI Key is PHXJVRSECIGDHY-UHFFFAOYSA-N. The molecular formula is C₂₉H₂₇F₃N₆O with molecular weight of 532.571 g/mol while the UNII is 4340891KFS. The Chemical name is Ponatinib (AP24534). It is a tyrokinase receptor inhibitor used in the medical treatment of refractory chronic myelogenous leukemia (CML) positive for the Philadelphia chromosome. The medication is generally characterized with short-lived elevations in serum aminotransferase levels for patients under treatment (Gover-Proaktor et al., 2015). Ponatinib is a benzamide manufactured by condensation of the carboxy group of 3-(imidazo[1,2 –b]pyridazin-3-ylethynyl)-4-methylbenzoic acid with the anilino group of  4-[(4-methylpiperazin-1-yl)methyl1]-3-(triflouromethyl)aniline. It functions as an antineoplastic agent and a tyrosine kinase inhibitor. It is a N-methylpiperazine, which is a member of benzamides, an acetylenic compound, an imidazopyridazine and a member of (trifluoromethyl)benzenes (Shamroe & Comeau, 2013).

Manufacturing Company, Indications, Administration, and Dosage.

Manufacturing Company, Indications, Administration, and Dosage

Ponatinib is FDA approved medicine which is manufactured by Incyte Biosciences Distribution B.V company. The drug is used to treat chronic myelold leukemia and acute Lymphonoblastic leukemia disorders which are characterized by the increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. For Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia, the recommended dose is 45 mg PO daily. It is also recommended that the doses should be continued as long there is no any evidence of disease progression or any form of unacceptable toxicity. The drug is not indicated or recommended for patients who are newly diagnosed with chronic myeloid leukemia. However, the dose can be modified by reducing it to 30mg per day when there are substantial issues such as renal and hepatic impairment. The drug is administered orally.

Pharmacology

Ponatinib is specified for treating adult patients who have blast phase chronic myeloid leukemia (CML), accelerated phase, or chronic phase which is intolerant or resistant to prior tyrosine kinase inhibitor therapy. Moreover, it is also used for the treatment of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) which is intolerant or impervious to prior tyrosine kinase inhibitor therapy (Shamroe & Comeau, 2013). Pomatinib is associated with conditions such as Blast phase chronic myelocytic leukemia, Chronic Phase Chronic Myeloid Leukemia, Accelerated phase chronic myologenic leukemia, and Acute Lymphoblastic Leukaemias (ALL).

Mechanism of Action

Ponatinib acts as a multi-target kinase inhibitor with its main or principal cellular target being the Bcr-Abl tyrosine kinase protein which is usually active and stimulates chronic myeloid leukemia (CML) progression. The Bcr-Abl tyrosine kinase protein results from the Abl gene and fused Bcr; what is universally called Philadelphia chromosome which plays critical role in the treatment of chronic myeloid leukemia. Ponatinib is subsumed as a very unique drug because it is particularly expedient and appropriate for treating resistant chronic myeloid leukemia (CML) since it deters the T315I mutant kinases and tyrosine kinase activity of Abl (Shamroe & Comeau, 2013). Notably, the mutation of T315I results in resistance in cells because it impedes or inhibits other inhibitors of Bcr-Abl from binding with the Abl kinase. Moreover, ponatinib also has other targets which it inhibits including members of the EPH, FGFR, PDGFR, VEGFR receptors. It also inhibits FLT3, TIE2, RET, and KIT and SRC families of kinases.  A reduction in tumor size which expresses T315I mutant BCR-ABL or native has been witnessed in rats.

Absorption

The drug is absorbed gently when taken orally, however, its absolute bioavailability is not known. It attains its utmost concentration in plasma within six hours after Iclusig oral administrations. In blood, it is 97.5% bound to plasma proteins and a half-life of 24 to 26 hours. Food consumption does not impact the absorption of the drug and its aqueous solubility depends on pH, with lower pH leading to high solubility (Nazha et al., 2015). When 45 mg of the drug is administered to a cancer patient, the pharmacokinetic parameters include; AUC = 1253 ng•hr/mL, Cmax = 73 ng/mL. The steady state volume of distribution of ponatinib is 1223 Liters in a one-day oral administration of 45 mg for about 28 days in a cancer patient. The drug is a weak substrate for ABCG2 as well as P-gp.

Metabolism

No less than 64 percent of a ponatinib dose goes through both the stage I and stage II of metabolism. It is vital to note that CYP3A4 and to a smaller extent and CYP3A5, CYP2D6, and CYP2C8 get involved in the stage I metabolic rate of ponatinib in vitro. The drug is as well broken down or metabolized by amidases and esterases. The major preliminary pathway of metabolism for ponatinib is N-demethylation. The molecule has plasma terminal elimination half-life of 61 to 105 hours. Both in vivo pharmacological and in vitro biochemical testing have revealed N-desmethylponatinib to be significantly less active than ponatinib.

Distribution

The drug is absorbed by achieving its maximum convention then it is distributed to the whole body. Studies indicate that it is more than 99% protein-bound in vitro (Shamroe & Comeau, 2013). According to the geometric mean, its steady volume of distribution is 1223 L (102 percent) preceding Iclusig 45mg oral administration once per day for twenty-eight day in patients having cancer.  The drug is a weak substrate for ABCG2, P-gp, and vitro and it is not one of the substrates for organic onions which transport polypeptides. 

Excretion or Elimination  

It is excreted largely as metabolites in feces and urine. Its geometric mean terminal excretion half-life is 24 hours preceding an oral administration of Iclusig 45mg once per day for 28 days. Close to 5 percent of a radioactive dose is usually recovered in urine and approximately 88 percent in feces.

Interaction

            Ponatinib interacts with several drugs such as CYP3A Inhibitors, CYP3A Inducers, and CYP Substrates.  Co-administration of a single 15 mg oral dose of ponatinib in the presence of a strong CYP3A Inhibitor such as ketoconazole (400mg daily) upsurges the Cmax and AUC0-∞ of ponatinib by 47% and 78%, respectively, in comparison of the oral administration of ponatinib alone. In regards to the co-administration of CYP3A Inducers and Ponatinib, because the human oxidative metabolic rate of ponatinib through the cytochrome P450 system principally or mainly encompasses CYP3 isozymes, a decrease in the exposure of ponatinib is in the offing and was detected in simulation through the use of a mechanistic model.

On the other hand, vitro studies indicate show that in co-administration of ponatinib with CYP Substrates, ponatinib fails to inhibit the metabolism of substrates for CYP2D6, CYP3A, CYP2C19, CYP1A2, CYP2C8, CYP2C9, or CYP2B6 and also fails to trigger the metabolism of substrates for CYP3A, CYP2B6, or CYP1A2. In co-administration with Substrates of Transporters, vitro studies show that ponatinib is an inhibitor of ABCG2 and P-gp as well as BSEP. Furthermore, in vitro, ponatinib never inhibited the organic cation transporters OAT3, OAT1, and OCT1, OCT2 or the human organic anion which transports polypeptides OATP1B3 or OATP1B1.

Contraindications

Ponatinib is contraindicated in patients with several conditions. Particularly, arterial occlusions have occurred in approximately 40 percent of ponatinib-treated patients. According to Wehrle,  Pahl,  and von Bubnoff  (2014), some patients experience more than one type of such events.  Some of the events include stroke, stenosis, myocardial infarction, and severe peripheral vascular disease. Additionally, venous thromboembolism has been witnessed in several people under this medication (Nazha et al., 2016). According to Gover-Proaktor et al. (2015), venous occlusive events occurs in iclusig-treated patients which results in venous thromboembolism. To prevent thromboembolism, it is important to consider discontinuation of the drug or its reduction in patients who have developed serious venous thromboembolism. Furthermore, cases of heart failure, which includes fatalities occurred in about 9 percent of individuals under this medication. It is in this context that doctors should monitor cardiac function. Örenay et al. (2014) says that it is important to interrupt or stop the medication for worsening or new cases of heart failure. Another contraindication of ponatinib is hepatotoxicity. Notably, death and failure of liver has occurred in several patients under ponatinib medication. Similarly, in such cases, the drug should be stopped immediately. Another contraindication which has been observed among the patients using Ponatinib is bleeding which may involve GI bleeding and intracranial bleeding. According to the study conducted by Örenay et al. (2014), serious bleeding has been observed with ponatinib therapy, which includes intracranial bleeding and GI bleeding where instances were fatal. The study reveals that “serious bleeding occurred frequently in patients with blast phase of chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. The majority of serious bleeding events occurred in patients who had grade 4 thrombocytopenia. Interrupt therapy and evaluate in patients who develop serious or severe bleeding”.

Side Effects

While its effects have been significant in treatment of chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia, Ponatinib has got certain side effects which patients should be ready for and report if such impacts become extreme and persist for a long period of time. Major side effects include dry mouth, drowsiness, loss of appetite, increased sweating, trouble sleeping, nausea, and increased sweating (Gover-Proaktor et al., 2015). A study conducted by Izgi et al. (2014) reveals that some of those side effects can be dangerous hence if they persist for long, the patient should immediately report to the doctor. The doctor can then decide to stop the medication or reduce its dosage depending on the extent of the side effects.

Conclusion

Cancer is among the leading causes of death which accounted for approximately 9.8 million deaths in the year 2018. One of the medicines that has been found to be effective in treating cancer diseases particularly chronic myelold leukemia and acute Lymphonoblastic leukemia is ponatinib. Ponatinib is a third-generation tyrosine 9TKIs) kinase inhibitor that is very active on patients with chronic myeloid leukemia (CML) and patients who are resistant to multiple tyrosine kinase inhibitor (TKIs. Ponatinib acts as a multi-target kinase inhibitor with its main or principal cellular target being the Bcr-Abl tyrosine kinase protein which is usually active and stimulates chronic myeloid leukemia (CML) progression. Major side effects include dry mouth, drowsiness, loss of appetite, increased sweating, trouble sleeping, nausea, and increased sweating. Some of the contraindications include arterial occlusions, thromboembolism, and hepatotoxicity.