Total anti-neoplastic agents approved in last 5 years r 43 . They can b classified broadle into 2 groups –first is cytotoxic drugs which act non-selectively and kill tumor cells as well as normal cells . Second group is targeted therapy which r relatively more selective act upon only its target. This target may b some gene muation, sum antigen and any signal transduction molecule. It is obvious that cytotoxic drugs act non-selectively so produce more ADRs than targeted therapy. Considering this, new and new drugs r cuming in this group.Out of 43 drugs, 32 r in targeted therapy while only 9 r in cytotoxic group
Bendamustine is nitrogen mustard which is bifunctional – have 2 functional group and so they are more potent than other alkylating agent that one functional group. It has benzimidazole or purine backbone.
Intermediate is ethyleneimonium ion that acts in 2 steps. Major site of alkylation is N7 position of guanine. Other sites include N1 , N3 positions of adenine, N3 of cytosine, O6 of Guanine and phosphate and proteins associted with DNA. Apart from cross-linking other MOA of bendamustine- mispairing of guanine sothat it can bind thymine inspite of cytosine, and may be opening of imidazole ring.
It has purine like structure thatwhy it has sum unique properties.
Alkylating agents are highly toxic to rapidly dividing cells and these cells are present in BM, hair follicle, germinal organs n intestinal wall. So their ADR are more related to these structures. Nausea , vomiting are more common in nitrogen mustard group.
First 4 drugs act upon microtubules that are formed in metaphase of M- phase of cell cylcle. Vincristine sulphate is a member of vinca alkaloids and congener of vinblastine n vinorelbine. Paclitaxel protein bound paticles, cabazitaxel are fm taxane group which has other congener.Cabazitaxel is non- hormonal anti-neoplastic approved for prostate cancer. L-asparaginase is an enzyme that is found more in leukemic cells. Ingenol is active agent in sap of australian plant Euphorbia.
Conventional vincristine is toc along with glucocorticoids to induce remission in pediatric ALL. Used dose is 2mg/m2 i.v. but in adults it is used as dose of 1.4mg/m2 . At that level too, it is less tolerated in adults than children who develop severe, progressive neurological toxicity. To make the vincristine more tolerated it is encapsulated in sphinomyelin/ cholesterol liposome. Which increases its efficacy and reduces its toxicity. Liposome has the same structure as of cell membrane. It has bilyaer of phospholipid in which hydrophic head is outside and i/s and hydrophobic tail is facing towards to each other.
It binds selectively to beta tubulin and blocks its polymerization to alpha tubulin in microtubules. So there is no intact microtubules are left in the cell so movement of duplicated chromosomes is restricted n they cant align along the division plate. So cell division comes to a halt and cell death occurs.
It has less ADR than conventional vincristine.
Non- small cell lung cancer makes up around 75% of all cases of lung cancer n includes squ cell ca, adenocat n large cell ca. when it is diagnosed in advanced form, prognosis is very poor. Surgery n radiotherapy are tried along with chemotherapy. In chemotherapy – “ platinum doublets” is used. In platinum compound cisplatin or carboplatin are chosen. In companion drug frequently paclitaxel is found efffective.
• Formulation & Dose – Sol for iv admin – Dose- 30 mg/m2 iv bolus once weekly for 6 weeks in 7 weeks cycles – Vitamin supplementation Folic acid 1mg – initiate 10 days prior Vit B12 im- 10 weeks prior & every 10 weeks03/07/13 12
Natural Products S.No. Name of Drug Approved for Year 1. VinCRIStine sulphate Ph- ALL Aug2012 liposomal injection 2 Paclitaxel protein-bound Non small cell lung Oct 2012 particles cancer 3 Cabazitaxel Prostate cancer June2010 4 Eribulin Metastatic breast Nov 2010 cancer 5 L-Asparaginase erwinia ALL Nov 2011 chrysanthemi 6 Ingenol Actinic Keratosis Jan201203/07/13 14
VinCRIStine Sulphate liposomal Inj• Approved for – Adults with Ph- ALL in second or greater relapse or whose disease has progressed following > 2 anti-leukemic drugs• Why liposomal preparation? – “Liposome makes it adult”03/07/13 15
• MOA – Cell cycle specific(v/s alkylating agents) – Polymerization of microtubules• Formulation & Dose – Solution for iv injection – Initial dose 2.25 mg/m2 iv over one hour weekly03/07/13 16
Paclitaxel protein-bound particle• Approved for – First line t/t of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in pt who are not candidates for curative surgery or radiation therapy03/07/13 18
• Why nab- preparation of paclitaxel? – To overcome limitations of conventional prep Poor acqueous solubility vehicle 50%ethanol + 50% polyethoxylated castor oil ( cremophor)• Advantage of nab-paclitaxel – No hypersensitivity – Less time in infusion03/07/13 19
• MOA – Promotes polymerization of microtubules – Binds to beta tubulin03/07/13 20
• Formulation & dose – Solution for iv infusion – Dose- 100mg/m2 as iv infusion over 30min on day 1, 8 and 15 of each 21days cycle – With carboplatin• ADR – Neutropenia – Neuropathy- more – Hypersensitivity- less – Fatigue03/07/13 21
Cabazitaxel• Approved for – t/t of hormone refractory prostate cancer pt – In combination with prednisone who have previously treated with docetaxel• MOA- same as paclitaxel03/07/13 22
• Formulation & Dose – Sol for iv use – 25 mg/m2 over every 3weeks – Oral prednisolone 10mg – Premedicate –antihistaminics, corticosterids• ADRs – N/V/D – Hematological Rxn – Hypersensitivity Rxn – Anorexia, Fatigue03/07/13 23
Eribulin• Approved for – t/t of metastatic breast cancer pt who have previously received atleast two chemotherapeutic regimens• Isolated from Helichondria okadai• MOA – Not well known – Acts on microtubules – Affects growth phase –03/07/13 No affect on shortening phase 24
• Formulation & dose – Solution for iv inj – 1.4mg/m2 iv over 2-5 min on day 1 & 8 of 21 days cycle• ADR – N/V/D – Hematological rxn – Hypersensitivity rxn – Anorexia, Fatigue•03/07/13 25
Asparaginase Erwinia chrysanthemi• Approved for – As a component of multi-agent chemotherapy for t/t of ALL who have developed hypersensitivity to E.coli derived asparaginase o Why aspaginase Erwinia chrysanthemi? Hypersensitivity Rxn 5-20% Gram negative rod bacteria 03/07/13 26
• MOA – Asparagine imp for protein synthesis – Lyphocytic leukemic cells lack asparagine synthetase – Degrades into metabolites03/07/13 27
• Formulation & dose – Solution for im use – 25000 IU three times a week for 8 weeks• ADRs – Hypersensitivity – Inhibition of protein synthesis Hyperglycemia Hypertriglyceridemia, Pancreatitis Thrombosis Hypoalbuminemia 28
IngenolApproved For Source- EuphorbiaActinic KeratosisFormulation & Dose MOA ADR0.015% or 0.05% gel for topical Inducer of -Local skin RxnFace, Scalp- once daily for 3 apoptosis & cell -Painconsecutive days 0.015% death -PruritisTrunk, Extremities- once daily for -unknown MOA -Infection2consecutive days 0.05%03/07/13 29
Hormones & its antagonistsS.No. Name of Drug Approved MOA Year For1 Enzalutamide Androgen 2012 receptor Metastatic inhibitor castration2 Degarelix GnRH 2008 resistant analogue prostate cancer3 Abiraterone Steroid 2011 synthesis inhibitor03/07/13 30
• Hormone therapy in prostate cancer• Androgen Deprivation Therapy – Surgical – Medical GnRH agonist- high dose/ continuous GnRH antagonist Androgen Receptor inhibitor03/07/13 31
Formulation & Dose Cap 80mg, 20 mg Dose 140 mg, without food ADRs GI distress Hair color changes Hypertension03/07/13 48
Inhibitors of AngiogenesisS. Name of Approved for YearNo. Drug1 Sunitinib Pancreatic NET 20112 Axitinib Advanced RCC 20123 Pazopanib Advanced RCC 2009 Advanced Soft tissue 2012 sarcoma4 Bevacizum Metastatic RCC in 2009 ab combination with iFN- alpha5 Ziv- Metastatic CRC with 2012 afilabercept FOLFIRI 51
MOA• Role of angiogenic factors – VEGF, PDGF, TGF-b, FGF• VEGF-most studied• Angiogenesis inhibitors – Binding of angiogenesis facors to its receptor activate the intracellular TK activity -- mitogenic and antiapoptotic pathway within endothelial cells-- cell proliferation03/07/13 52
Everolimus• Approved by FDA for – Advanced RCC after failure of Suniti-/Sorafenib- 2009 – Progressive Pancratic NET with unresectable or metastatic disease- 2011 – Renal Angiomyolipoma associated with tuberous sclerosis- 2012 – Hormone receptor +, her2 - Ca Breast after failure of t/t with letrozole ,anastrozole- 201203/07/13 58
Plerixafor• Approved for – In combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in pt with NHL & MM03/07/13 66
• Transplantation of hematopoitic stem cells• Indication• Source – BM – Peripheral blood• Role of interaction of CXCR4 & SDF-1• MOA of Plerixafor – Hematopoietic stem cells are mobilized in peripheral blood03/07/13 67
• Formulation – Solution for sc• Dose – Given sc after 4 days of G-CSF t/t – Dose 0.24mg/kg• ADRs – Injection site reactions – GI distress – Fatigue, headache, dizziness03/07/13 68
Pomalidomide• Approved for – Pt with MM who have received atleast 2 prior therapies including lenalidomide & bortezomib and have demonstrated disease progression within 60 days of last therapy03/07/13 69
• Formulation & Dose – IV infusion 50 million autologous CD54+ cells activated with PAP, GM-CSF designed – 3 completed doses at 2 weeks interval• ADRs – Flu like Chills, headache, fever03/07/13 75
Recombinant Bivalent HPV Vaccine• Recombinant vaccine that contains L1 protein, major antigenic protein of HPV type 16 & type18• Approved for – Prevention of the CIN & cervical cancer• Formulation & Dose – Suspension for im inj – 3 doses, 0.5 ml, at 0,1 , 6 months03/07/13 76
Monoclonal AntibodiesS.No. Name of Drug Approved for Year1. Trastuzumab Gastric cancer Oct 20102. Ado- trastuzumab Metastatic breast Feb 22, 2013 cancer3. Ofatumumab CLL Oct 20094. Pertuzumab Her+ metastatic June 2012 breast cancer5. Denosumab Prevention of Nov 2010 metastatic skeletal related events6. Ipilimumab Metastaic melanoma March 20117. Brentuximab HL, anaplastic large August 201103/07/13 79 cell lymphoma
Trastuzumab• Approved for – t/t of her+ overexpressing metastatic gastric or gastroesophageal adenocarcinoma in combination with cisplatin & capecitabine or 5-FU who have not received prior t/t for it03/07/13 80
• ADRs – Immunosuppresion Reactivation of viral infections Not with hepatitis B infection URTI, pneumonia – Myelosuppresion – Hypersensitivity03/07/13 87
Pertuzumab• Approved for – t/t of her+ metastatic breast cancer (+ trastuzumab and docetaxel)• MOA – Similar to trastuzumab03/07/13 88
• Formulation & Dose – 420 mg/ 14 ml vial iv infusion – Initial Dose-840 mg administered as 60 min iv infusion• Maintenance dose- 420 mg administered in 30-60min• ADRs – GI Distress – Neutropenia – Neuropathy – Rashes03/07/13 89
Denosumab• Approved for – prevention of skeletal related events in pt with bone metastasis• Tumor with common bone metastasis – In adults – In children• MOA – Binds to RANKL – RANK present on osteoclast03/07/13 90
Ipillitumumab• Approved for – t/t of metastatic melanoma• MOA – Blockade of CTLA-4 – CTLA-4 suppresses immune response03/07/13 92
• Formulation & Dose – Sol for iv – 3mg/ kg iv over 90 mins every 3 weeks total 4 doses• ADRs – Fatigue – Diarrhea – Rash, Pruritus – Colitis03/07/13 93
Brentuximab• Approved for – HL After failure of autologous stem cell transplant, or, After failure of atleast 2 prior multiagent chemotherapy regimen – Systemic anaplastic large cell lymphoma After failure of one prior multiagent chemotherapy regimen03/07/13 94
• Formulation & Dose – Sol for iv infusion – Dose 1.8 mg/kg over 30 min• ADRs – GI Distress – Myelosupression – Neuropathy03/07/13 96
OthersS.No. Name of Drug Approved For Year1 Carfilzomib MM 20122 Romidepsin Cutaneous T-cell 2009 lymphoma3 Vismodegib BCC 20124 Omacetaxine CML 20125 Vemurafenib Melanoma 201103/07/13 97
Carfilzomib• Approved for – t/t of MM in pt who have received atleast 2 prior therapies (+ bortezomib & immunomodulators) & have demonstrated disease progression within 60 days of completion of last therapy03/07/13 98