IBRITUMOMAB          73          cancer is reaching plateau due to several side effects and low cure rate.          Severa...
74      ICATIBANT          cytotoxicity and complement-dependent cytotoxicity. The drug also          helps to promote apo...
IMATINIB MESYLATE           75          2.      Icatibant. Merck Manual http://www.gmerk.net/Icatibant.html.              ...
76      IMIQUIMOD                                            Table                          Other Drugs with Related Mecha...
IPILIMUMAB        77          been in clinical use for more than a decade. Imiquimod 5% cream has          proven to be an...
78      LAPATINIB          2.      Pennock GK, Waterfield W, Wolchok JD. Patient responses to                  Ipilimumab,...
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Exclusive preview newer drug 2e by vikas dhikav


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• Since this is a second edition. It contains added new drugs which have been discovered in the last 4 years.
• Study of newer drugs takes lot of time, and there is no unified source of newer drugs. One has to extract such information from bigger books like
Current Medical Diagnosis and Treatment, Harrisons’ Principles of Internal Medicine, or books of pharmacology like Katzung’s/Goodman & Gillman’s.
• Present book is very useful from the point of view that it contains new drugs and students don’t have to slog for information regarding newer drugs in different books. It contains comprehensive information.
• It is also very useful for the practitioners and PG students .This book gives them edge by having the recent information about the new drugs

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  1. 1. IBRITUMOMAB 73 cancer is reaching plateau due to several side effects and low cure rate. Several new therapeutic targets have been described, and epidermal growth factor receptor (EGFR) is one of them. Gefitinib1 is one of many inhibitors of tyrosine kinase, like erlotinib and sunitinib. It is the selective inhibitor of tyrosine kinase of epidermal growth factor (EGF) by binding to ATP-binding site. This type of receptor is expressed in certain cancers like breast and lung cancers. Occasionally, it undergoes mutation in cancers. It is this mutation that has been shown to activate anti-apoptotic pathways in certain non–small cell lung cancers. It is approved for the treatment of small cell lung cancer in patients who have previously received chemotherapy. Since it is a selective chemotherapeutic agent, therefore its safety is far superior to most agents used as anticancer agents. It is emerging as an important treatment for both locally invasive and metastatic variety of non–small cell lung cancer, particularly in those harboring mutations of EGFR mutations.2 Side Effects Nausea, vomiting, anorexia, stomatitis, rashes, etc, are the non-specific side effects. Acne is the most common side effects. References 1. Birnbaum A, Ready N. Gefitinib therapy for non–small cell lung cancer. Curr Treat Options Oncol 2005;6:75–81. 2. Sanford M, Scott LJ. Gefitinib: a review of its use in the treatment of locally advanced/metastatic non–small cell lung cancer. Drugs 2009;69:2303–28. doi: 10.2165/10489100-000000000-00000. IBRITUMOMAB Ibritumomab is a monoclonal antibody. It is a radiopharmaceutical agent useful in the treatment—as part of therapeutic regimen, including rituximab—of relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma, including patients with rituximab-refractory patients. The drug binds to CD20 antigens and initiates mounting of an immune attack involving antibody-dependentNewer Drug 2e.indd 73 10/21/2011 5:13:53 PM
  2. 2. 74 ICATIBANT cytotoxicity and complement-dependent cytotoxicity. The drug also helps to promote apoptosis. Radioimmunotherapy, targeting the CD20 antigen, in B-cell lymphoma has clearly demonstrated efficacy and tolerability over the preceding 15 years. Two products are available with the FDA approval for marketing—90Y-ibritumomab tiuxetan and 131I-tositumomab. Both demonstrate high-response rates and durability of remission in the relapsed/refractory disease setting.1 Reference 1. Davies AJ. Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I(131) tositumomab. Oncogene 2007;26:3614–28. ICATIBANT B radykinin is a local hormone and involved in the regulation of many major physiological systems. Superficially, its actions resemble to that of histamine, i.e., causes vasodilatation, increases capillary permeability, and smooth muscle contraction occurs. Icatibant, a 10-amino acid peptide, is a selective and specific bradykinin receptor antagonist of bradykinin-2 receptors (B2). It can blunt blood pressure lowering effects of captopril. Presently, it is an orphan drug used mainly for acute attacks of hereditary angioedema. In this condition, there are recurrent attacks of angioedema of skin, larynx, and GI tract. It has been seen that bradykinin is a key mediator of inflammation leading to generation of symptoms. Icatibant has a modified peptide structure and is the first bradykinin receptor antagonist to act on the guinea pig trachea without demonstrating agonist effects.1 The drug is also touted to be beneficial in drug-induced angioedema and capillary leak syndrome.2 Though increases in the levels of bradykinin have been demonstrated in burns, liver diseases, and allergic and inflammatory disorders, role of icatibant is not clear. Recently, injection of icatibant for acute attacks of hereditary angioneurotic edema was approved.3 References 1. Anonymous. Icatibant: HOE 140, JE 049, JE 049. Drugs R D 2004;5:343–8.Newer Drug 2e.indd 74 10/21/2011 5:13:53 PM
  3. 3. IMATINIB MESYLATE 75 2. Icatibant. Merck Manual http://www.gmerk.net/Icatibant.html. Accessed January 2011. 3. http://www.drugs.com/newdrugs.html. IMATINIB MESYLATE Late 1990s have seen a revolutionary change in drug therapy for cancers due to arrival of imatinib. After ABL-BCR translocation and Philadelphia chromosomes have been described, investigators wanted to find out a drug that could inhibit that protein. Cancer treatment has so far been restricted to cytotoxic and hormonal agents. These are plagued by their limited efficacy and their toxicity profile. A key target being actively pursued is the receptor tyrosine kinase. Several compounds that inhibit this target are in preclinical and clinical development. These compounds broadly fall into 2 categories: monoclonal antibodies and small-molecule inhibitors. The common targets are epidermal growth factor receptor, ABL-BCR tyrosine kinase, vascular endothelial growth factor, fibroblast growth factor receptor, and platelet-derived growth factor. Two of these compounds, trastuzumab and imatinib mesylate, have been approved by the US FDA for use in specific indications.1 Imatinib is a phenylaminopyridine derivative and is a specific inhibitor of tyrosine kinase domain in ABL-BCR and platelet-derived growth factor. It decreases ABL-BCR activity seen in Philadelphia chromosome. As an exact step, the drug binds competitively with ATP, and this interferes with ABL-BCR function.2 Given orally, imatinib has good oral absorption. It is metabolized by cytochromal enzymes and elimination is via bile. It has a potential to inhibit cytochromal enzymes; therefore, potential to inhibit microsomal enzymes should be kept in mind. Half-life is around 24 hours. Imatinib is the drug of choice for the treatment of chronic myeloid leukemia and stromal tumors. It is also getting investigated for a number of other medical conditions such as pulmonary hypertension, hypereosinophilic syndrome, and dermatofibrosarcoma. Several other tyrosine kinase inhibitors have been approved or are under clinical development (see below).Newer Drug 2e.indd 75 10/21/2011 5:13:53 PM
  4. 4. 76 IMIQUIMOD Table Other Drugs with Related Mechanisms Gefitinib Sunitinib Sorafenib Erlotinib Dasatinib Lapatinib Nilotinib Imatinib is given conveniently as oral tablets of 100 and 400 mg. Side Effects Side effects are non-specific and include nausea, vomiting, diarrhea, ocular pain, fluid retention, and rashes. Possibility of infections is increased. Thrombocytopenia, neutropenia, and anemia can occur. Uncommonly, fluid retention can be severe enough to precipitate congestive cardiac failure. References 1. Goel S, Mani S, Perez-Soler R. Tyrosine kinase inhibitors: a clinical perspective. Curr Oncol Rep 2002;4:9–19. 2. Croom KF, Perry CM. Imatinib mesylate: in the treatment of gastrointestinal stromal tumours. Drugs 2003;63:513–22; discussion 523–4. IMIQUIMOD Genital warts are sexually transmitted and are caused by human papilloma virus. These are some of the most common—and yet least talked about—sexually transmitted diseases. It is spread by sexual contact with an infected partner and is highly contagious. Imiquimod is a synthetic imidazoquinoline heterocyclic amine. Imiquimod is a cytokine inducer and a modifier of the innate immune response, as well as of acquired antiviral and antitumor immune responses. Though, exact mechanism of action of imiquimod is not known, it activates immune cells, which in turn secrete a number of cytokines. It is believed to act on “toll-like receptors” that play an important role in pathogen recognition by immune cells. The drug hasNewer Drug 2e.indd 76 10/21/2011 5:13:53 PM
  5. 5. IPILIMUMAB 77 been in clinical use for more than a decade. Imiquimod 5% cream has proven to be an effective treatment for external genital warts, Bowen’s disease, superficial basal cell carcinoma, and actinic keratosis.1 Reference 1. Vidal D. Topical imiquimod: mechanism of action and clinical applications. Mini Rev Med Chem 2006;6:499–503. IPILIMUMAB Lymphocyte activation and uncontrolled proliferation are the characteristics of many malignant disorders. However, cytotoxic immune cells play a vital role in clearing cancerous cells. Ipilimumab, humanized monoclonal antibody (IgG1), binds to cytotoxic T-cell lymphocyte antigen, which suppresses T-lymphocyte response. By inhibiting this antigen, the drug boosts activity of cytotoxic T lymphocytes, which are in turn able to kill tumor cells. This drug therefore is an immunopotentiator. This has been found to be useful in treating unresectable or metastatic melanomas. A total of 4 doses are given IV in dose of 3 mg/kg for 90 minutes. Dose interval between 2 doses is 3 weeks. Though it has been approved clinically for melanoma, it is undergoing clinical trials for hormone-refractory prostate cancer and for both small cell and non–small cell lung cancers.1 It is noteworthy that advanced melanoma has defied treatment for decades. It has conventionally been treated with interleukin-2 or interferon-α.2 Side Effects The GI side effects including diarrhea and colitis have occurred in clinical trials. References 1. Mori T. Ipilimumab, a new molecular targeted therapy of malignant neoplastic disease. Gan To Kagaku Ryoho 2011;38:31–5.Newer Drug 2e.indd 77 10/21/2011 5:13:54 PM
  6. 6. 78 LAPATINIB 2. Pennock GK, Waterfield W, Wolchok JD. Patient responses to Ipilimumab, a novel immunopotentiator for metastatic melanoma: how different are these from conventional treatment responses? Am J Clin Oncol 2011. [Epub ahead of print]. LAPATINIB Lapatinib is a dual inhibitor1 of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (EGFR [ErbB-1]) and human epidermal receptor type 2 (HER-2 [ErbB-2]) receptors. Mutations in either of these receptors have been shown to play a role in cancer. The overexpression of EGFR and HER-2 has been associated with a number of cancers, including breast cancer. Lapatinib is specifically indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER-2 and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Importantly, the drug could be given as monotherapy2 and in combination with trastuzumab. Lapatinib is available as 250 mg tablets for oral administration. The recommended initial dose of the drug is 1250 mg (5 tablets) given orally once daily on days 1–21 continuously in combination with capecitabine 2000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on days 1–14 in a repeating 21-day cycle. Cautious use is indicated in patients with left ventricular dysfunction. Patients with severe hepatic impairment should have their dose reduced. The concomitant use of strong CYP3A4 inhibitors and inducers should be avoided. Side effects are mild to moderate in severity and most are reversible. It is a well-tolerated drug overall. References 1. Montemurro F, Valabrega G, Aglietta M. Lapatinib: a dual inhibitor of EGFR and HER2 tyrosine kinase activity. Expert Opin Biol Ther 2007;7:257–68. 2. Moy B, Goss PE. Lapatinib: current status and future directions in breast cancer. Oncologist 2006;11:1047–57.Newer Drug 2e.indd 78 10/21/2011 5:13:54 PM