Your SlideShare is downloading. ×
0
Anti-Neoplastic Agents Approved       by FDA in Last Five Years             (2008-till now)             Dr Nitin Kothari03...
Antineoplastic Agents in Last Five                Years03/07/13    Total Drugs= 43            2
Cytotoxic Agents      – Alkylating Agents      – Antimetabolites      – Natural Products      – Hormones & its antagonists...
Alkylating Agents-Bendamustine• Approved in year 2008 for      – CLL- efficacy to first line drugs?      – NHL- progressed...
• Not a true ‘-mustine’( carmustine)03/07/13                               5
MOA03/07/13         6
• Unique properties      – Cross-link repair slow      – Lacks resistance to other alkylators      – Significant activity ...
• Dose regimen                CLL                NHL           100 mg/m2 I.V. over   120 mg/m2 I.V. over           30 min ...
• ADR      – BM toxicity      – Mucosal toxicity-            stomatitis,            intestinal denudation      – Reprodu...
Anti-metabolites-Pralatrexate• Approved for      – t/t of pt with relapsed or refractory peripheral        T-cell lymphoma...
Pralatrexate           PRALATREXAT                Purine Synthesis                E03/07/13                           11
• Formulation & Dose      – Sol for iv admin      – Dose- 30 mg/m2 iv bolus once weekly for 6        weeks in 7 weeks cycl...
Pralatrexate• ADRs      – BM - Myelosuppression            Anemia      – Infection      – Haemorrhage      – Intestine   ...
Natural Products S.No.          Name of Drug                Approved for      Year 1.        VinCRIStine sulphate       Ph...
VinCRIStine Sulphate liposomal Inj• Approved for      – Adults with Ph- ALL in second or greater        relapse or whose d...
• MOA      – Cell cycle specific(v/s alkylating agents)      – Polymerization of microtubules• Formulation & Dose      – S...
• ADR      – GI distress            Bulk forming laxative as prophylaxis            Diarrohea      – Peripheral neuropat...
Paclitaxel protein-bound particle• Approved for      – First line t/t of locally advanced or metastatic        non-small c...
• Why nab- preparation of paclitaxel?      – To overcome limitations of conventional prep            Poor acqueous solubi...
• MOA      – Promotes polymerization of microtubules      – Binds to beta tubulin03/07/13                                 ...
• Formulation & dose   – Solution for iv infusion   – Dose- 100mg/m2 as iv infusion over 30min on     day 1, 8 and 15 of e...
Cabazitaxel• Approved for      – t/t of hormone refractory prostate cancer pt      – In combination with prednisone who ha...
• Formulation & Dose   – Sol for iv use   – 25 mg/m2 over every 3weeks   – Oral prednisolone 10mg   – Premedicate –antihis...
Eribulin• Approved for   – t/t of metastatic breast cancer pt who have     previously received atleast two     chemotherap...
• Formulation & dose      – Solution for iv inj      – 1.4mg/m2 iv over 2-5 min on day 1 & 8 of 21        days cycle• ADR ...
Asparaginase Erwinia                chrysanthemi• Approved for  – As a component of multi-agent chemotherapy    for t/t of...
• MOA      – Asparagine imp for protein synthesis      – Lyphocytic leukemic cells lack asparagine        synthetase      ...
• Formulation & dose  – Solution for im use  – 25000 IU three times a week for 8 weeks• ADRs  – Hypersensitivity  – Inhibi...
IngenolApproved For                         Source- EuphorbiaActinic KeratosisFormulation & Dose                   MOA    ...
Hormones & its antagonistsS.No. Name of Drug Approved            MOA         Year                   For1          Enzaluta...
• Hormone therapy in prostate cancer• Androgen Deprivation Therapy      – Surgical      – Medical            GnRH agonist...
DEGARELIX                           ABIRATERONEENZALUTAMIDE03/07/13                           32
• Degarelix      – Avoids “flare” phenomenon of GnRH agonist      – Precursor – Abarelix• Enzalutamide      – Potency & li...
• Abiraterone      – Non-gonadal source of androgen            Adrenal gland            Prostate cancer cells      – Blo...
S. Name of               Formulation           DoseNo. Drug                 Available1          Degarelix     Powder for  ...
• ADRs of ADTs( Degarelix & Abiraterone)      – Hot flushes           - Hypertension      – Loss of libido        - UTI   ...
• ADRs of Enzalutamide      – Asthenia(>5%)      – Fatigue      – Arthralgia      – Musculosketal pain      – Headache    ...
Targeted Therapeutic Agents•   TK inhibitors•   mTOR inhibitors•   Inhibitors of angiogenesis•   Immunomodulators•   Monoc...
Tyrosine Kinase InhibitorS.No. Name of Drug      Approved for       Year1          Bosutinb     Ph+ CML            20122  ...
Bosutinib• Congener of Imatinib• Approved for      – Ph+ CML with resistance to prior therapies03/07/13                   ...
03/07/13   41
• Formulation & Dose      – Tablet for oral admn      – Dose 500 mg once daily03/07/13                         42
•   Drug interaction•   Protease inhibitors•   Azoles antifunguals    Common to                           D, I, N•   Antie...
• ADRs ( common with congeners)      – GI distress      – Myelosuppression      – Liver problems      – Fluid retention   ...
Crizotinib• MOA   – Dual inhibitor       C-Met-GF       ALK-TK• Formulation & Dose   – Tablet for oral admn   – 250 mg t...
Vandetanib• MOA      – TK R inhibitors            VEGF            EGF• Formulation & Dose      – Tablet for oral admn   ...
Cabozantinib• MOA      – Pan-tyrosine kinase inhibitor            RET,MET,KIT            VEGFR-1,2,3            TRKB, F...
Formulation & Dose             Cap 80mg, 20 mg             Dose 140 mg, without             food           ADRs           ...
Inhibitors of AngiogenesisS.    Name of     Approved for           YearNo.   Drug1     Sunitinib   Pancreatic NET         ...
MOA• Role of angiogenic factors      – VEGF, PDGF, TGF-b, FGF• VEGF-most studied• Angiogenesis inhibitors      – Binding o...
•   Sunitinb- VEGF-R, PDGF-R•   Axitinib- VEGF-R 1, 2 ,3•   Pazopanib- VEGF-R 1, 2 ,3•   Ziv-afilabercept- VEGF, Placental...
ADRs common to angiogenesis              Inhibitors• Potential for vessel injury & bleeding      – Pulmonary haemorrhage<2...
• Hypertension      – Reason- decreased eNO      – Antihypertensive drugs      – Complications            Reversible post...
• Sunitinib ( pan TK-I)      – Fatigue- 50-70%      – Hypothyroid- 40%      – Severe neutropenia- 10%• Recommendations    ...
• Axitinib      – GI distress      – Palmer planter keratosis• Pazopanib      – Dysguesia, Dyspnoea      – Skin hypopigmen...
Everolimus• Approved by FDA for      – Advanced RCC after failure of        Suniti-/Sorafenib- 2009      – Progressive Pan...
Everolimus: MOA                             Raf03/07/13                           59
• Formulation & Dose      – 5mg, 10 mg tablet      – Dose-            10 mg once daily            Can be increased by 5 ...
• ADR      – Common ( 30-50%)            Maculopapuar rash            Mucositis            Anemia            Fatigue  ...
ImmunomodulatorsS.N Name of Drug            Yearo.1   Peg-interferon alpha-   2011    2b2   Plerixafor              20083 ...
Peginterferon alpha 2b• Approved for      – Adjuvant t/t of melanoma with nodal        involvemont within 84 days of defin...
• MOA      – Pleiotropic cytokine• Formulation      – Powder for reconstitution, sc• Dose      – Initial-6mcg/kg/week eigh...
• ADRs      – Flu like symptoms            Fever, chills, headache            Fatigue, myalgia      – Liver03/07/13     ...
Plerixafor• Approved for      – In combination with G-CSF to mobilize        hematopoietic stem cells to the peripheral   ...
• Transplantation of hematopoitic stem cells• Indication• Source      – BM      – Peripheral blood• Role of interaction of...
• Formulation      – Solution for sc• Dose      – Given sc after 4 days of G-CSF t/t      – Dose 0.24mg/kg• ADRs      – In...
Pomalidomide• Approved for      – Pt with MM who have received atleast 2 prior        therapies including lenalidomide & b...
Pomalidomide03/07/13                  70
• Formulation      – Capsule for oral administration• Dose      – 4 mg once daily without food on day 1-21 of        repea...
• ADRs      – No sedation      – Less constipation      – No sensory neuropathy      – Myelosuppression            Anemia...
Sipuleucel- T• Autologus immunotherapy      – Against PAP• Approved for      – Asymptomatic or minimally symptomatic      ...
Sipuleucel-T           (Provenge)03/07/13                  74
• Formulation & Dose      – IV infusion 50 million autologous CD54+ cells        activated with PAP, GM-CSF designed      ...
Recombinant Bivalent HPV                   Vaccine• Recombinant vaccine that contains L1  protein, major antigenic protein...
• ADRs      – Local reactions            Pain, redness, swelling      – Fatigue, headache, myalgia03/07/13               ...
• Formulation & Dose      – Tablet for oral admn- 240 mg• Dose-      – 4 tablets twice daily atleast gap of 12 hours• ADRs...
Monoclonal AntibodiesS.No.          Name of Drug   Approved for           Year1.         Trastuzumab        Gastric cancer...
Trastuzumab• Approved for      – t/t of her+ overexpressing metastatic gastric        or gastroesophageal adenocarcinoma i...
MOA03/07/13         81
• Formulation & Dose      – Sol for iv dose      – 8mg/kg 90 min iv infusion      – Followed by 6 mg/kg over 30-90 min in ...
• ADRs      – Immunogenic            Fever, chills, rashes            Premedication      – Cardiac Toxicity            ...
Ado- trastuzumab• Approved for her2+ metastatic breast  cancer• MOA      – DM1 interferes cell growth• ADRs      – Nausea,...
Ofatumumab• Approved for      – t/t of pt with CLL refractory to fludarabine and        alemtuzumab03/07/13               ...
• Formulation- 20mg/ml           • Regimen- 12 dose             – Ist dose-300mg 1st               week             – Dose...
• ADRs      – Immunosuppresion            Reactivation of viral infections            Not with hepatitis B infection    ...
Pertuzumab• Approved for      – t/t of her+ metastatic breast cancer (+        trastuzumab and docetaxel)• MOA      – Simi...
• Formulation & Dose   – 420 mg/ 14 ml vial iv infusion   – Initial Dose-840 mg administered as 60 min iv     infusion• Ma...
Denosumab• Approved for      – prevention of skeletal related events in pt with        bone metastasis• Tumor with common ...
• Formulation & Dose      – sc preparation      – 120 mg every 4 weeks• ADRs      – Fatigue      – Hypophoshatemia      – ...
Ipillitumumab• Approved for      – t/t of metastatic melanoma• MOA      – Blockade of CTLA-4      – CTLA-4 suppresses immu...
• Formulation & Dose      – Sol for iv      – 3mg/ kg iv over 90 mins every 3 weeks total 4        doses• ADRs      – Fati...
Brentuximab• Approved for      – HL            After failure of autologous stem cell transplant, or,            After fa...
• MOA      – Antibody-drug conjugate03/07/13                          95
• Formulation & Dose      – Sol for iv infusion      – Dose 1.8 mg/kg over 30 min• ADRs      – GI Distress      – Myelosup...
OthersS.No. Name of Drug          Approved For       Year1          Carfilzomib      MM                 20122          Rom...
Carfilzomib• Approved for      – t/t of MM in pt who have received atleast 2        prior therapies (+ bortezomib &       ...
MOA• NF-KB – cell survival & proliferation• IkB is degraded by proteasome- NF-KB  promotes cell proliferation      CARFIL...
• Formulation & Dose      – 28 days t/t cycle      – For 3 weeks, given on 2 consecutive days in        each week followed...
• ADRs      – Fatigue      – Thrombocytopenia      – Anemia      – Diarrhoea      – Pyrexia      – No peripheral neuropath...
Romidepsin• Approved for      – Cutaneous T-cell lymphoma who have        received atleast one prior systemic therapy03/07...
Acetylation---- transcription           increases           Deacetylation----           transcription decreases         ...
• Formulation & Dose      – Sol for iv      – 14 mg/m2 over 4 hour period on day 1, 8and        15 of a 28 day cycles     ...
• ADRs      – GIT distress            N/V/ D      – Anorexia      – Fatigue      – Pyrexia03/07/13               105
Vismodegib• Approved for      – t/t of adults with metastatic or locally        advanced BCC that has recurred following  ...
Vismodegib• MOA      – Inhibitor of Hedgehog signaling pathway03/07/13                                          107
• Formulation & Dose      – Tablets for oral admin      – 150 mg once daily untill disease progression        of toxicity•...
Omacetaxine• Approved for      – t/t of adults with CML with resistance to        atleast 2 TKI• MOA      – Protein synthe...
• Formulation & Dose      – Solution for sc           Induction Scedule     Maintenance dose           1.25 mg/m2 s.c.    ...
• ADRs      – Myelosuppression            Anemia            Neutropenia            Thrombocytopenia      – Fatigue     ...
Vemurafenib• Approved for      – Unresectable or metastatic metastatic        melanoma with BRAF V600E mutation03/07/13   ...
Vemurafenib                         Raf03/07/13                       113
Drugs Approved for MM             Peg-interferon03/07/13                           114
THANK YOU03/07/13               115
Upcoming SlideShare
Loading in...5
×

Antineoplastic seminar

297

Published on

This seminar presentation on recent antineoplastic agents.

Published in: Education
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
297
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
15
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide
  • 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.
  • Source-australian plant euphorbia pelpus.
  • Cauda equina syndrom Asthenia fatigue –mc adr &gt;5% pt
  • ALK=anaplastic lymphoma kinase
  • 4ebp= eukaryotic initiation factor -4E binding protein
  • Interferon a is protein degraded by enzme and reduce its antigenicty it is combined with PEG.
  • SDF1=stromal derived factor1
  • Red letters mean inhibit these processes, Green letters mean promotes these reactions
  • RANKL=receptor associted nuclear factor kappa ligand
  • CTLA-4= cytotoxic T lymphocyte associated antigen 4
  • Transcript of "Antineoplastic seminar"

    1. 1. Anti-Neoplastic Agents Approved by FDA in Last Five Years (2008-till now) Dr Nitin Kothari03/07/13 1
    2. 2. Antineoplastic Agents in Last Five Years03/07/13 Total Drugs= 43 2
    3. 3. Cytotoxic Agents – Alkylating Agents – Antimetabolites – Natural Products – Hormones & its antagonists03/07/13 3
    4. 4. Alkylating Agents-Bendamustine• Approved in year 2008 for – CLL- efficacy to first line drugs? – NHL- progressed during or within 6 months of t/t with rituximab or rituximab with CHOP03/07/13 4
    5. 5. • Not a true ‘-mustine’( carmustine)03/07/13 5
    6. 6. MOA03/07/13 6
    7. 7. • Unique properties – Cross-link repair slow – Lacks resistance to other alkylators – Significant activity CLL & other lymphoma• Formulation – Powder 100mg vial , reconstitution, – iv infusion03/07/13 7
    8. 8. • Dose regimen CLL NHL 100 mg/m2 I.V. over 120 mg/m2 I.V. over 30 min on day 1, 2 60 min on day 1, 2 on 28 days cycle on 21 days cycle upto 6 cycles upto 8 cycles03/07/13 8
    9. 9. • ADR – BM toxicity – Mucosal toxicity-  stomatitis,  intestinal denudation – Reproduction – Alopecia – Nausea, vomiting03/07/13 9
    10. 10. Anti-metabolites-Pralatrexate• Approved for – t/t of pt with relapsed or refractory peripheral T-cell lymphoma• Congener of Mtx03/07/13 10
    11. 11. Pralatrexate PRALATREXAT Purine Synthesis E03/07/13 11
    12. 12. • 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
    13. 13. Pralatrexate• ADRs – BM - Myelosuppression  Anemia – Infection – Haemorrhage – Intestine – Nausea, Constipation03/07/13 13
    14. 14. 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
    15. 15. 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
    16. 16. • 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
    17. 17. • ADR – GI distress  Bulk forming laxative as prophylaxis  Diarrohea – Peripheral neuropathy – Anemia – Febrile neutropenia – Pyrexia03/07/13 17
    18. 18. 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
    19. 19. • 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
    20. 20. • MOA – Promotes polymerization of microtubules – Binds to beta tubulin03/07/13 20
    21. 21. • 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
    22. 22. 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
    23. 23. • 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
    24. 24. 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
    25. 25. • 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
    26. 26. 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
    27. 27. • MOA – Asparagine imp for protein synthesis – Lyphocytic leukemic cells lack asparagine synthetase – Degrades into metabolites03/07/13 27
    28. 28. • 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
    29. 29. 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
    30. 30. 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
    31. 31. • Hormone therapy in prostate cancer• Androgen Deprivation Therapy – Surgical – Medical  GnRH agonist- high dose/ continuous  GnRH antagonist  Androgen Receptor inhibitor03/07/13 31
    32. 32. DEGARELIX ABIRATERONEENZALUTAMIDE03/07/13 32
    33. 33. • Degarelix – Avoids “flare” phenomenon of GnRH agonist – Precursor – Abarelix• Enzalutamide – Potency & libido maintained – Precursor- Flutamide, Bicalutamide03/07/13 33
    34. 34. • Abiraterone – Non-gonadal source of androgen  Adrenal gland  Prostate cancer cells – Block CYP-17 ( 17 α hydroxylase) – Congener- Ketoconazole03/07/13 34
    35. 35. S. Name of Formulation DoseNo. Drug Available1 Degarelix Powder for Initial- 240mg reconstitution 120mg, Maintenance- sc 80 mg /month2 Abiraterone Tablet 1000mg3 Enzalutamide Oral Capsule 40 mg 4 capsules once03/07/13 35
    36. 36. • ADRs of ADTs( Degarelix & Abiraterone) – Hot flushes - Hypertension – Loss of libido - UTI – Impotence - Diarrohea( Abiraterone) – Gynecomastia – Anemia – Weight gain – ↓ insulin sensitivity – Altered lipid profile – Osteoporosis, fracture, loss of muscle mass 3603/07/13
    37. 37. • ADRs of Enzalutamide – Asthenia(>5%) – Fatigue – Arthralgia – Musculosketal pain – Headache – Dizziness – LRTI – Spinal cord compression03/07/13 37
    38. 38. Targeted Therapeutic Agents• TK inhibitors• mTOR inhibitors• Inhibitors of angiogenesis• Immunomodulators• Monoclonal antibodies• Others03/07/13 38
    39. 39. Tyrosine Kinase InhibitorS.No. Name of Drug Approved for Year1 Bosutinb Ph+ CML 20122 Crizotinb ALK + Non small 2011 cell lung cancer3 Vandetanib Metastatic MCT 20114 Cabontanib Metastatic MCT 201203/07/13 39
    40. 40. Bosutinib• Congener of Imatinib• Approved for – Ph+ CML with resistance to prior therapies03/07/13 40
    41. 41. 03/07/13 41
    42. 42. • Formulation & Dose – Tablet for oral admn – Dose 500 mg once daily03/07/13 42
    43. 43. • Drug interaction• Protease inhibitors• Azoles antifunguals Common to D, I, N• Antiepileptics• PPI Common• Antacid to Dasatinib03/07/13 43
    44. 44. • ADRs ( common with congeners) – GI distress – Myelosuppression – Liver problems – Fluid retention – Others  Rash No QT prolongation  Pyrexia ( Nilotinib)  Fatigue03/07/13 44
    45. 45. Crizotinib• MOA – Dual inhibitor  C-Met-GF  ALK-TK• Formulation & Dose – Tablet for oral admn – 250 mg twice daily• ADRs – GI Distress-N/V/D/C – Vision disorders03/07/13 45
    46. 46. Vandetanib• MOA – TK R inhibitors  VEGF  EGF• Formulation & Dose – Tablet for oral admn  300 mg once daily• ADRs – GI distress – Headache, fatigue03/07/13 46
    47. 47. Cabozantinib• MOA – Pan-tyrosine kinase inhibitor  RET,MET,KIT  VEGFR-1,2,3  TRKB, FLT-3,AXL, TIE-203/07/13 47
    48. 48. Formulation & Dose Cap 80mg, 20 mg Dose 140 mg, without food ADRs GI distress Hair color changes Hypertension03/07/13 48
    49. 49. 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
    50. 50. 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
    51. 51. • Sunitinb- VEGF-R, PDGF-R• Axitinib- VEGF-R 1, 2 ,3• Pazopanib- VEGF-R 1, 2 ,3• Ziv-afilabercept- VEGF, Placental GF• Bevacizumab- Antibody against VEGF03/07/13 53
    52. 52. ADRs common to angiogenesis Inhibitors• Potential for vessel injury & bleeding – Pulmonary haemorrhage<2% – C/I  Bleeding diathesis  Hemoptysis  Brain metastasis – Operation should be avoided03/07/13 54
    53. 53. • Hypertension – Reason- decreased eNO – Antihypertensive drugs – Complications  Reversible posterior leucoencepalopathy  CCF03/07/13 55
    54. 54. • Sunitinib ( pan TK-I) – Fatigue- 50-70% – Hypothyroid- 40% – Severe neutropenia- 10%• Recommendations – Regular blood examination – Thyroid test – ECG03/07/13 56
    55. 55. • Axitinib – GI distress – Palmer planter keratosis• Pazopanib – Dysguesia, Dyspnoea – Skin hypopigmentation, hair color change• Ziv-aflibercept – Liver – Kidney03/07/13 57
    56. 56. 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
    57. 57. Everolimus: MOA Raf03/07/13 59
    58. 58. • Formulation & Dose – 5mg, 10 mg tablet – Dose-  10 mg once daily  Can be increased by 5 mg( max dose 20 mg)03/07/13 60
    59. 59. • ADR – Common ( 30-50%)  Maculopapuar rash  Mucositis  Anemia  Fatigue – Less common  Leucopenia,Thrombocytopenia  Hyper-glycemia, -triglyceridemia  Pulmonary infilterates03/07/13 61
    60. 60. ImmunomodulatorsS.N Name of Drug Yearo.1 Peg-interferon alpha- 2011 2b2 Plerixafor 20083 Pomalidomide Feb 08,20134 Sipuleuceucel-T 2010 ( Provenge)5 Recombinant HPV 2009 Type 16, 18 Vaccine (Cervarix) 62
    61. 61. Peginterferon alpha 2b• Approved for – Adjuvant t/t of melanoma with nodal involvemont within 84 days of definitive surgical resection( + lymphadenectomy)• Why PEGylation?03/07/13 63
    62. 62. • MOA – Pleiotropic cytokine• Formulation – Powder for reconstitution, sc• Dose – Initial-6mcg/kg/week eight doses – Then 3mcg/kg/week upto 5 years – Premedicate with PCM03/07/13 64
    63. 63. • ADRs – Flu like symptoms  Fever, chills, headache  Fatigue, myalgia – Liver03/07/13 65
    64. 64. 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
    65. 65. • 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
    66. 66. • 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
    67. 67. 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
    68. 68. Pomalidomide03/07/13 70
    69. 69. • Formulation – Capsule for oral administration• Dose – 4 mg once daily without food on day 1-21 of repeated 28 days cycles untill disease progression03/07/13 71
    70. 70. • ADRs – No sedation – Less constipation – No sensory neuropathy – Myelosuppression  Anemia  Neutropenia – Fatigue, asthenia03/07/13 72
    71. 71. Sipuleucel- T• Autologus immunotherapy – Against PAP• Approved for – Asymptomatic or minimally symptomatic metastatic hormone refractory prostate cancer03/07/13 73
    72. 72. Sipuleucel-T (Provenge)03/07/13 74
    73. 73. • 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
    74. 74. 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
    75. 75. • ADRs – Local reactions  Pain, redness, swelling – Fatigue, headache, myalgia03/07/13 77
    76. 76. • Formulation & Dose – Tablet for oral admn- 240 mg• Dose- – 4 tablets twice daily atleast gap of 12 hours• ADRs – Skin menifestation  rash, skin papilloma, pruritis, photosensitivity03/07/13 78
    77. 77. 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
    78. 78. 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
    79. 79. MOA03/07/13 81
    80. 80. • Formulation & Dose – Sol for iv dose – 8mg/kg 90 min iv infusion – Followed by 6 mg/kg over 30-90 min in every 3 weeks untill disease progression03/07/13 82
    81. 81. • ADRs – Immunogenic  Fever, chills, rashes  Premedication – Cardiac Toxicity  Most serious, Fatal, 1%  Baseline ECG, Cardiac ejection fraction  careful follow-up- signs of CCF•03/07/13 83
    82. 82. Ado- trastuzumab• Approved for her2+ metastatic breast cancer• MOA – DM1 interferes cell growth• ADRs – Nausea,constipation, – Headache, myalgia, fatigue Liver Toxicity, Heart Toxicity Birth defects – Raised liver enzymes03/07/13 84
    83. 83. Ofatumumab• Approved for – t/t of pt with CLL refractory to fludarabine and alemtuzumab03/07/13 85
    84. 84. • Formulation- 20mg/ml • Regimen- 12 dose – Ist dose-300mg 1st week – Dose 2-8-2gm/week – Dose 9-12-2gm/4 weeks • Infusion rate – Dose 1-3.6mg/hr – Dose 2-24mg/hr – Dose3-12-50mg/hr03/07/13 86
    85. 85. • ADRs – Immunosuppresion  Reactivation of viral infections  Not with hepatitis B infection  URTI, pneumonia – Myelosuppresion – Hypersensitivity03/07/13 87
    86. 86. Pertuzumab• Approved for – t/t of her+ metastatic breast cancer (+ trastuzumab and docetaxel)• MOA – Similar to trastuzumab03/07/13 88
    87. 87. • 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
    88. 88. 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
    89. 89. • Formulation & Dose – sc preparation – 120 mg every 4 weeks• ADRs – Fatigue – Hypophoshatemia – Nausea03/07/13 91
    90. 90. Ipillitumumab• Approved for – t/t of metastatic melanoma• MOA – Blockade of CTLA-4 – CTLA-4 suppresses immune response03/07/13 92
    91. 91. • 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
    92. 92. 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
    93. 93. • MOA – Antibody-drug conjugate03/07/13 95
    94. 94. • Formulation & Dose – Sol for iv infusion – Dose 1.8 mg/kg over 30 min• ADRs – GI Distress – Myelosupression – Neuropathy03/07/13 96
    95. 95. 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
    96. 96. 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
    97. 97. MOA• NF-KB – cell survival & proliferation• IkB is degraded by proteasome- NF-KB promotes cell proliferation CARFILZOMIB β 503/07/13 99
    98. 98. • Formulation & Dose – 28 days t/t cycle – For 3 weeks, given on 2 consecutive days in each week followed by rest – Cycle 1- dose 20mg/m2---- 27mg/m203/07/13 100
    99. 99. • ADRs – Fatigue – Thrombocytopenia – Anemia – Diarrhoea – Pyrexia – No peripheral neuropathy – No Hypotension03/07/13 101
    100. 100. Romidepsin• Approved for – Cutaneous T-cell lymphoma who have received atleast one prior systemic therapy03/07/13 102
    101. 101. Acetylation---- transcription increases Deacetylation---- transcription decreases Romidepsin Increases Transcription03/07/13 103
    102. 102. • Formulation & Dose – Sol for iv – 14 mg/m2 over 4 hour period on day 1, 8and 15 of a 28 day cycles – Cycle repeated till relief or toxicity03/07/13 104
    103. 103. • ADRs – GIT distress  N/V/ D – Anorexia – Fatigue – Pyrexia03/07/13 105
    104. 104. Vismodegib• Approved for – t/t of adults with metastatic or locally advanced BCC that has recurred following surgery or who are not candidates for surgery or radiation03/07/13 106
    105. 105. Vismodegib• MOA – Inhibitor of Hedgehog signaling pathway03/07/13 107
    106. 106. • Formulation & Dose – Tablets for oral admin – 150 mg once daily untill disease progression of toxicity• ADRs – GI distress- N/V/ D/ C, appetite, wt loss – Dysguesia, Aguesia – Muscle spasm, Arthralgia, Fatigue03/07/13 108
    107. 107. Omacetaxine• Approved for – t/t of adults with CML with resistance to atleast 2 TKI• MOA – Protein synthesis inhibitor – Binds to A-site of peptidyl transferase03/07/13 109
    108. 108. • Formulation & Dose – Solution for sc Induction Scedule Maintenance dose 1.25 mg/m2 s.c. 1.25 mg/m2 s.c. Twice daily Twice daily 14 consecutive days 07 consecutive days In 28 days cycle In 28 days cycle03/07/13 110
    109. 109. • ADRs – Myelosuppression  Anemia  Neutropenia  Thrombocytopenia – Fatigue – Asthenia – Pyrexia03/07/13 111
    110. 110. Vemurafenib• Approved for – Unresectable or metastatic metastatic melanoma with BRAF V600E mutation03/07/13 112
    111. 111. Vemurafenib Raf03/07/13 113
    112. 112. Drugs Approved for MM Peg-interferon03/07/13 114
    113. 113. THANK YOU03/07/13 115
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×