Benchmark-Approved Drug by the FDA

Choose a drug that has been approved by the FDA within the past year.

Write a 1,000-1,250-word paper in which you:

Describe the drug approved by the FDA. Include the pharmacodynamics and pharmacokinetic properties of the chosen drug.Benchmark-Approved Drug by the FDA

Provide an overview of the disease state for which the drug is used.

Describe what is different about this agent compared to currently available therapies.

Discuss the potential risks associated with this agent and any monitoring parameters that are necessary.

Decide whether you would personally prescribe this agent or stick with currently available alternatives.

You are required to cite five to 10 sources to complete this assignment. Sources must be published within the last 5 years and appropriate for the assignment criteria and nursing content.

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Prepare this assignment according to the guidelines found in the APA Style Guide, located in the Student Success Center. An abstract is not required.

This assignment uses a rubric. Review the rubric prior to beginning the assignment to become familiar with the expectations for successful completion.

You are required to submit this assignment to Lopes Write. Refer to the Lopes Write Technical Support articles for assistance.

This assignment benchmarks the following competencies:

MS-NUR-ACNP

6.3: Assess the pharmacodynamics and the pharmacokinetic impact of pharmacologic therapies in the treatment of diseases and altered states.

7.3: Prescribe appropriate pharmacologic and nonpharmacologic therapies in the management of illness, disease, or injuries.

MS-NUR-FNP

6.3: Assess the pharmacodynamics and the pharmacokinetic impact of pharmacologic therapies in the treatment of diseases and altered states.

7.3: Prescribe appropriate pharmacologic and nonpharmacologic therapies in the management of illness, disease, or injuries.

Alpelisib (Piqray) is kinase inhibitors that inhibits phosphatidylinositol 3-kinase alpha (PI3Kα). Alpelisib, a drug manufactured by Novartis, is among the latest drugs that received their approval from Food and Drug Administration (FDA). Alpelisib is indicate in combination with fulvestrant to treat metastatic breast cancer in patients with human receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) and PIK3- mutation.(Markham, 2019)

The main mechanism of action of Alpelisib is through inhibition of PI3K. PI3K is a oncogene kinase that phosphorylates phosphatidylinositol 4, 5 bisphosphate (PIP2) to active phosphatidylinositol 3, 4, 5 trisphosphate (PIP3). PIP3 then acts as second massager to activate AKT, that later activates intracellular proteins that have an overall effect of activating genes responsible cell proliferation, growth and survival of cells. (Fruman et al., 2017; Fruman & Rommel, 2011; Vadas et al., 2011). Alpelisib has an advantage over the other forms of PIK3 inhibitors due to the fact it has 50 times affinity to PI3Kα than the rest of PI3K inhibitors.(André et al., 2019)Benchmark-Approved Drug by the FDA

In breast cancer and most solid tumors, PI3K oncogene is mutated. This creates an overall effect of continuous phosphorylation of PIP2 to PIP3 that has a positive downstream effect on cell proliferation, growth and survival. PIP3 formed after growth factor signal is rapidly metabolized by tumor lipid phosphatases such as PTEN. In most cancer, this PTEN, a tumor suppressor is lost. This leds to continuous phosphorylation of PIP2 to PIP3 leading to downstream transduction that ultimately led to cell proliferation, growth, survival and differentiaton. (Fruman et al., 1998, 2017; Fruman & Rommel, 2011; Vadas et al., 2011)

Alpelisib and fulvestrant was approved for use in men and postmenopausal women patients with breast cancer having PIK3CA mutations.(Angarita et al., 2020). Patients with PI3KCA mutation are the ideal candidates for treatment with alpelisib. Alpelisib can also be used to treat ovarian cancers caused by BRCA wild-type and are resistant to platinum chemotherapy. This trial showed an increase response rate by 33% when combine with olaparib in treatment. (Konstantinopoulos et al., 2019). Apelisib can also be used as monotherapy in treatment of most advance solid tumors, and has been shown to have an overall response rate of 3% with a median progression-free survival of 3.4 months.(Ando et al., 2019)

Alpelisib is an oral drug given in the dosage of 150mg or 300mg. In clinical trial of four healthy adults, Alpelisib was shown to have a bioavailability of 50%. The maximum concentration (T max) was 2 hours and elimination half-life time was 13.7hours. The volume of distribution was predicted to be approximately 114 (60%), with 89% protein binding capacity. There was minimal metabolism by cytochrome enzymes in the liver. Almost 79.8% of administered alpelisib was excreted via feces, while 13.1% was excreted via urine. Approximately 38.2% of alpesilib was excreted unchanged.(James et al., 2015)

In another clinical study conducted in March 2010 to March 2018, to compare the use of “Alpelisib plus Fulvestrant in PIK3KCA altered and PIK3KCA-wild-type estrogen receptor positive advance breast cancer’ the pharmacodynamics of alpelisib was analyzed; it was shown that there was minimal change in the cardiac electrophysiology with or without fulvestrant. The major side effects experienced in 10% of the patients were hyperglycemia (22%) and maculopapular rash (13%). The median progression- free survival was much higher for PIKCA altered tumors vs the wild-type tumors, with an average increase of 5 months.(Juric et al., 2019)

Alpselisib has been shown to have different side effects; some are tolerable while other require immediate discontinuation of treatment. Some of the side effects that require prompt and permanent discontinuation of main side effect of alpelisib are severe hypersensitivity reactions and severe cutaneous reactions. Other side effects include hyperglycemia, pneumonitis, diarrhea and embryo-fetal toxicity.(Goldenberg, 2004)

Findings from SOLAR-1 phase 3 randomized clinical trial showed alpesilib plus fulvestrant was more effective than placebo plus fulvestrant in patients with advance breast cancer that has endocrine positive and HER2-negative. These patients had been on aromatase inhibitors treatment prior to the clinical trial. Patients who had PI3KCA mutation and were on alpesilib and fulvestrant had 11 months progression-free survival (PFS), while those who were on placebo had a 5.7 months PFS. This finding proved the effectiveness of alpesilib in management of advance breast cancers that have high mutations of PI3KCA, and was the basis which FDA approved this drug.(Goldenberg, 2004)Benchmark-Approved Drug by the FDA

Due the different side effects experienced and expected after administration of alpelisib, it is advisable to monitor the progress of patient both though physical examination and laboratory investigations. It is advisable to have regular physical examination of patients to note any kind of hypersensitivity or cutaneous reactions to make a decision discontinue alpelisib depending on the extent of cutaneous damage.(Goldenberg, 2004)

Serial radiographic imaging to the chest is note development of severe progression of pneumonitis. Fasting plasma glucose and hemoglobin 1Ac test are done before the initiation of alpelisib. Alpelisib has been shown to cause hyperglycemia; therefore, serial random blood sugar is also done to monitor blood sugar level. Other biochemical test done include kidney profile test and liver function test.(Goldenberg, 2004)

In conclusion, several studies have shown alpelisib and fulvestrant are more effective than previous forms to treatment in advance breast cancer. They have also shown an overall increase in progression-free survival in patients with PI3KCA mutant breast cancer. The fact that this has a considerable safety profile, make it more favorable to use. Most of the expected side effects can be overcomed by simple and easy clinical practice. For example, hyperglycemia can be managed by dosage reduction or administration of antidiabetic. (Goldenberg, 2004; Juric et al., 2019)

Based on the above findings, I would confidently advocate the use of alpelisib in combination with fulvestrant in management of patients with advance breast cancer, with confirmed PI3KCA mutation. This drug will go a long way to improve the survival to my patients who are in their last line of therapy. I would also choose alpelisib due to the fact most of the side effects experienced are easily manageable. Lastly, the fact that alpelisib has been shown to have minimal drug-drug interaction, this can be advantageous to my elderly who most likely have existing comorbidities.

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                                                               References

  1. Ando, Y., Iwasa, S., Takahashi, S., Saka, H., Kakizume, T., Natsume, K., Suenaga, N., Quadt, C., & Yamada, Y. (2019). Phase I study of alpelisib (BYL719), an α-specific PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Science, 110(3), 1021–1031. https://doi.org/10.1111/cas.13923

André, F., Ciruelos, E., Rubovszky, G., Campone, M., Loibl, S., Rugo, H. S., Iwata, H., Conte, P., Mayer, I. A., Kaufman, B., Yamashita, T., Lu, Y.-S., Inoue, K., Takahashi, M., Pápai, Z., Longin, A.-S., Mills, D., Wilke, C., Hirawat, S., & Juric, D. (2019).  Alpelisib for PIK3CA -Mutated, Hormone Receptor–Positive Advanced Breast Cancer . New England Journal of Medicine, 380(20), 1929–1940. https://doi.org/10.1056/nejmoa1813904

Angarita, S., Ye, L., Rünger, D., Hadaya, J., Baker, J. L., Dawson, N., Thompson, C. K., Lee, M. K., Attai, D. J., & DiNome, M. L. (2020). Assessing the Burden of Nodal Disease for Breast Cancer Patients with Clinically Positive Nodes: Hope for More Limited Axillary Surgery. Annals of Surgical Oncology. https://doi.org/10.1245/s10434-020-09228-5

Fruman, D. A., Chiu, H., Hopkins, B. D., Bagrodia, S., Cantley, L. C., & Abraham, R. T. (2017). The PI3K Pathway in Human Disease. In Cell (Vol. 170, Issue 4, pp. 605–635). Cell Press. https://doi.org/10.1016/j.cell.2017.07.029

Fruman, D. A., Meyers, R. E., & Cantley, L. C. (1998). Phosphoinositide kinases. In Annual Review of Biochemistry (Vol. 67, Issue 1, pp. 481–507). https://doi.org/10.1146/annurev.biochem.67.1.481

Fruman, D. A., & Rommel, C. (2011). PI3Kδ inhibitors in cancer: Rationale and serendipity merge in the clinic. Cancer Discovery, 1(7), 562–572. https://doi.org/10.1158/2159-8290.CD-11-0249

Goldenberg, M. M. (2004). Pharmaceutical-approval update. In P and T (Vol. 29, Issue 8, pp. 507–509). MediMedia, USA. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705475/

James, A., Blumenstein, L., Glaenzel, U., Jin, Y., Demailly, A., Jakab, A., Hansen, R., Hazell, K., Mehta, A., Trandafir, L., & Swart, P. (2015). Absorption, distribution, metabolism, and excretion of [14C]BYL719 (alpelisib) in healthy male volunteers. Cancer Chemotherapy and Pharmacology, 76(4), 751–760. https://doi.org/10.1007/s00280-015-2842-4Benchmark-Approved Drug by the FDA

Juric, D., Janku, F., Rodón, J., Burris, H. A., Mayer, I. A., Schuler, M., Seggewiss-Bernhardt, R., Gil-Martin, M., Middleton, M. R., Baselga, J., Bootle, D., Demanse, D., Blumenstein, L., Schumacher, K., Huang, A., Quadt, C., & Rugo, H. S. (2019). Alpelisib Plus Fulvestrant in PIK3CA -Altered and PIK3CA -Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncology, 5(2), 184475. https://doi.org/10.1001/jamaoncol.2018.4475

Konstantinopoulos, P. A., Barry, W. T., Birrer, M., Westin, S. N., Cadoo, K. A., Shapiro, G. I., Mayer, E. L., O’Cearbhaill, R. E., Coleman, R. L., Kochupurakkal, B., Whalen, C., Curtis, J., Farooq, S., Luo, W., Eismann, J., Buss, M. K., Aghajanian, C., Mills, G. B., Palakurthi, S., … Matulonis, U. A. (2019). Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. The Lancet Oncology, 20(4), 570–580. https://doi.org/10.1016/S1470-2045(18)30905-7

Markham, A. (2019). Alpelisib: First Global Approval. Drugs, 79(11), 1249–1253. https://doi.org/10.1007/s40265-019-01161-6

Vadas, O., Burke, J. E., Zhang, X., Berndt, A., & Williams, R. L. (2011). Structural biology structural basis for activation and inhibition of class I phosphoinositide 3-kinases. In Science Signaling (Vol. 4, Issue 195). American Association for the Advancement of Science. https://doi.org/10.1126/scisignal.2002165

Benchmark-Approved Drug by the FDA