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הוראה בנושאי טיפול תרופתי בסרטן

הוראה בנושאי טיפול תרופתי בסרטן. השפעות גומלין בין תרופתיות ובין תרופות לקרינה ערך: פרופ’ נ. חיים , מאי 2003, עודכן- נובמבר 2004 כתובת לשאלות והערות: n_haim@rambam.health.gov.il. Interactions with 5FU & 5FU prodrugs. Cisplatin…. Interferons…. Lecovorin (l isomer )…. DPD inhibitors

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הוראה בנושאי טיפול תרופתי בסרטן

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  1. הוראה בנושאי טיפול תרופתי בסרטן השפעות גומלין בין תרופתיות ובין תרופות לקרינה ערך: פרופ’ נ. חיים , מאי 2003, עודכן- נובמבר 2004 כתובת לשאלות והערות: n_haim@rambam.health.gov.il

  2. Interactions with 5FU & 5FU prodrugs • Cisplatin…. • Interferons…. • Lecovorin (l isomer)…. • DPD inhibitors • Methotrexate…. • PALA…. • Allopurinol…. • Warfarin (coumadin) & 5FU/capecitabine…. • Sorivudine and oral 5FU prodrugs…. • Capecitabine and oxaliplatin…. • Radiation therapy….

  3. Synergism between cisplatin and 5FU Possible mechanisms include cisplatin-mediated enhanced DNA damage, and interference with repair of cisplatin-DNA adducts.

  4. Synergism between Interferons (IFNs) and 5FU • IFN alpha enhances the activity of 5FU • Mechanism uncertain. Possible mechanisms: -increased FdUMP formation -enhanced 5FU metabolism -decreased 5FU clearance

  5. Modulation of 5FU action by leucovorin Leucovorin stabilizes the FdUdMP-TS-folate ternary complex (a stable covalent complex with TS).

  6. Modulation of 5FU by DPD inhibitors • Uracil (in UFT): inhibits DPD… • Eniluracil: a pyrimidine analog that lacks antitumor activity of its own; inactivates DPD by forming a covalent bond that permanently alters the active site of the enzyme. When given with oral 5FU inhibits degradation of 5FU within the GIT (and increases bioavailability to approximately 100%). • S1 : Oral formulation composed of ftorafur, 5-chloro-2,4-dihydropyridine (=reversible DPD inhibitor) and oxonic acid (protects from incorporation of 5FU metabolites into RNA of normal GIT tissue). See review:Schmoll HJ. Anti-Cancer Drugs 14: 695-702, 2003

  7. Modulation of 5FU by Methotrexate When given before 5FU, MTX-mediated inhibition of DHFR results in accumulation of PRPP. Increased availability of PRPP promotes formation of FUMP…with enhanced FUTP incorporation into RNA.

  8. Modulation of 5FU by PALA • PALA is an inhibitor of of aspartate transcarbamylase, enzyme in de novo pyrimidine synthesis. • When given before 5FU-increased formation of FUTP and increased incorporation (=misincorporation) into RNA.

  9. Modulation of 5FU toxicity by allopurinol • In-vitro, allopurinol was shown to selectively block biochemical pathways for activating 5FU in normal tissues. • Clinical trials (including allopurinol mouthwashes to prevent mucositis): no convincing evidence for protective effect.

  10. Interaction between 5FU & Warfarin (Coumadin) Kolesar JM et al. Pharmacotherapy 19: 1445-9, 1999: • 5 pts received concomitant warfarin and 5FU. All pts required a warfarin dosage reduction; 2 were hospitalized (one with a major bleeding) • The etiology of such interaction is not clear (possible explanations: 5FU may interfere with warfarin degradation by inhibiting cytochrome P450 3A4(CYP3A4)).

  11. Interaction between 5FU & Warfarin (Coumadin) given in “mini-dose” • Minidose warfarin (1 mg/day) was given for prophylaxis of central venous catheter-associated thrombosis in patients treated with 5FU-based chemotherapy. • INR elevation (>1.5) occurred in 33% of the patients )(minidose heparin is not expected to cause significant alterations in PT or PTT).INR elevation was especially evident in FOLFOX treated pts. Masci G et al. J Clin Oncol 21:736-9,2003 Magagnoli M et al.Ann Oncol 14: 959-60,2003 (letter)

  12. Interaction between Capecitabine & Warfarin (Coumadin) Same as with 5FU: few cases reported. Copur MS et al. Clinical Colorectal Cancer 1: 182-4, 2001(2 cases) Buyck HCE et al. Clinical Oncology 15: 1, 2003 (letter) (2 cases)

  13. Interaction between sorivudine (an anti-viral drug) and oral 5FU prodrugs Okuda H et al. Drug metab dispos 25: 270-3, 1997: • The study was performed in rats to investigate a mechanism responsible for fatal toxicity reported in 15 Japanese patients treated with tegafur and sorivudine, given PO. • Bromovinyl uracil generated from sorivudine by gut flora is reduced in the presence of NADPH to a reactive form by hepatic DPD, binds covalently to DPD and inhibits 5FU metabolism.

  14. Capecitabine and oxaliplatin In a human xenograft model, the combination of capecitabine and oxaliplatin was synergistic….oxaliplatin upregulated thymidine phosphorylase (TP) expression in CXF280 tumor tissue (see also: “Interaction between capecitabine and taxanes”)…. Cassidy J et al. J Clin Oncol 22: 2084-91, 2004 (the same paper also reports on XELOX as active first-line for pts with metastatic colon cancer).

  15. Synergism between 5FU and radiation therapy • 5FU (as other fluoropyrimidines) enhances the cytotoxicity of ionizing irradiation: • possible mechanisms: -increased DNA damage -inhibition of DNA repair -accumulation of cells in S phase

  16. Interactions with methotrexate • Leucovorin…. • Drugs that are cleared by tubular secretion…. • Nephrotoxic drugs: vancomycin….cisplatin: see cisplatin…. • Drugs that bind to protein…. • Vincristine: see vinca alkaloids….

  17. Interactions with methotrexate: antagonism with leucovorin Leucovorin (tetrahydrofolate) is antagonist of methotrexate…

  18. Pharmacokinetic drug interactions with methotrexate • Renal clearance of methotrexate: Glomerular filtration Tubular secretion Tubular reabsorption • Aspirin, penicillins, cephalosporines, NSAIDs: these drugs (weak acids) are excreted by active tubular secretion, and, therefore, compete with methotrexate for active tubular secretion.

  19. Possible pharmacokinetic interaction: Prior vancomycin and impairment of high-dose methotrexate clearance Blum R et al. Ann Oncol 13: 327-30, 2002 • In 2 pts significant decrease in HD-MTX clearance and subclinical renal impairment (documented by impaired GFR by technechium 99m diethylene triamine penta-acetic acid scanning) developed following vancomycin. Shamash J et al. Ann Oncol 14: 169-70, 2002 (letter) • The suggestion that a repeat EDTA should be performed following vancomycin administration if high-dose MTX is used again , cannot be supported by their experience (8 pts).

  20. Drug interaction due to protein-binding: methotrexate-sulphonamides & phenytoin Interaction between methotrexate /, sulphonamides, and phenytoin: Increased toxicity of MTX due to protein-binding displacement by these drugs.

  21. Interactions with gemcitabine • Cisplatin…. • Radiation therapy…. • Docetaxel: See: Taxanes….

  22. Synergism between gemcitabine and cisplatin Thought to be mainly due to an increase in platinum DNA adduct formation, which in turn results from dFdC incorporation into DNA

  23. Synergism between gemcitabine and radiation therapy • Gemcitabine is radiosensitizer and , theoretically, may be effective in combined modality therapy. • However, because gemcitabine is a potent radiation sensitizer, increased toxicity could be a serious problem….

  24. Interactions with cisplatin/carboplatin • Etoposide…. • Gemcitabine: see gemcitabine…. • 5FU: see 5FU…. • Paclitaxel: see taxanes…. • drugs eliminated through kidneys…. • Trastuzumab (Herceptin)…. • Oxaliplatin/capecitabine: see: “Interactions with 5FU & 5FU prodrugs”…. • Radiation therapy….

  25. Interactions between cisplatin and etoposide Synergistic action….frequently used in combination….

  26. Possible pharmacokinetic interactions of cisplatin with drugs eliminated through kidneys Delayed excretion of methotrexate, bleomycin, ifosfamide (when given following or with cisplatin)

  27. Interaction between cisplatin & herceptin • Herceptin was found to be in-vitro synergistic with cisplatin. • The combination of herceptin and cisplatin is clinically active.

  28. Synergism between cisplatin and radiation therapy • Cisplatin (and also carboplatin) is radiosensitizer. • Possible mechanism: by forming DNA-cross linking inhibits repair of sublethal and potentially lethal radiation damage.

  29. Interaction with taxanes • Paclitaxel/doxorubicin…. • Inducers of CYP450…. • Inhibitors of CYP450…. • Paclitaxel/cisplatin…. • Paclitaxel/carboplatin…. • Taxol/herceptin • Docetaxel/estramustine phosphate • Taxanes/capecitabine…. • Dcetaxel/Gemcitabine…. • Taxanes (given PO)/cyclosporine…. • Possible synergism between paclitaxel and cyclo-oxygenase-2 (COX-2) inhibitors • Paclitaxel/warfarin….

  30. Metabolic/pharmacokinetic interaction between paclitaxel and doxorubicin Prior administration of paclitaxel reduces doxorubicin clearance due to inhibition of doxorubicin liver clearance (possibly competition for biliary excretion of taxanes and anthracyclines mediated by p-gp). Gianni L et al. J Clin Oncol 15: 1906-15, 1997

  31. Metabolic/pharmacokinetic interaction between paclitaxel and doxorubicin & increased cardiotoxicity Higher incidence of CHF at cumulative doxorubicin doses more than 380 mg/m2, probably due to a metabolic/pharmacokinetic interaction, resulting in decreased elimination of doxorubicin. Gianni L et al. Ann Oncol 12: 1067-73, 2001

  32. Metabolic/pharmacokinetic interaction between paclitaxel/docetaxel and drugs affecting Cytochrome P-450 metabolism Inducers of cytochrome P-450 mixed function oxidases (anticonvulsants,e.g. phenytoin, phenobarbital): theoretically, accelerated metabolism and increased clearance (same interaction is ,theoretically, possible with etoposide, doxorubicin, irinotecan)

  33. Metabolic/pharmacokinetic interaction between paclitaxel/docetaxel and drugs affecting Cytochrome P-450 metabolism • potential interaction of paclitaxel- also with inhibitors of cytochrome p-450 mixed function oxidases (cimetidine, erythromycin, fluconazole, corticosteroids) • theoretically, impaired metabolism and decreased clearance (same interaction is, theoretically, possible with etoposide, doxorubicin, irinotecan)

  34. Pharmacokinetic interaction between paclitaxel and cisplatin The sequence of cisplatin followed by paclitaxel (24 hrs schedule) induces more profound neutropenia than the reverse sequence (33% reduction of paclitaxel clearance when given after cisplatin).

  35. Pharmacodynamic interaction of unknown reason: Paclitaxel & Carboplatin Carboplatin: there is no pharmacokinetic interaction, but there is a pharmacodynamic, platelet -sparing effect (“protective effect of paclitaxel”) on this dose-limiting toxicity of carboplatin (paclitaxel given before carboplatin). Kearns CM & Egorin MJ. Semin Oncol 24: s2-91-s2-96, 1997 Belani CP et al. J Clin Oncol 17: 676-684, 1999

  36. Pharmacodynamic interaction of unknown reason -Taxol/Herceptin & cardiac dysfunction Seidman A et al. J Clin Oncol 20: 1215-21, 2002 • עבודה רטרוספקטיבית על 1219 חולות שטופלו בהרספטין במחקרים phase II&III. Rate of cardiac dysfunction: - ADM/CTX/Herceptin=27% - ADM/CTX=8% -Taxol/Herceptin=13% -Taxol=1% - Herceptin=3-7%

  37. Interaction between estramustine phosphate and docetaxel • Preliminary evidence has been found that the coadministration of oral estramustine phosphate and docetaxel significantly impairs the clearance of the latter (need to reduce docetaxel dose when administered in combination with estramustine phosphate). Petrylak DP et al. J Clin Oncol 17: 958-67,1999 • Estramustine, (which disrupts microtubule-associated proteins in vitro), has synergistic activity with docetaxel against human prostate-cancer cell lines. Kreis W et al. Br L Urol 79: 196-202, 1997 • The combination of estramustine phosphate and docetaxel has been found active in metastatic hormone refractory prostate cancer. Petrylak DP et al. N Engl J Med 351: 1513-20, 2004

  38. Interaction between capecitabine and taxanes • Preclinical synergy: -In human xenografts paclitaxel and docetaxel have been demonstrated to induce thymidine phosphorylase (TP) activity. TP upregulation may increase the metabolic activation of capecitabine). (Sarvada N et al. Clin Cancer Res 4: 1013-19, 1998). -On the other hand: preclinical studies showed that capecitabine can inhibit expression of Bcl-2, a key antiapoptotic mediator (Suzuki K et al. Jpn J Clin Oncol 29: 323-31, 1999). Downregulation of Bcl-2 will enhance taxane activity. contd

  39. Interaction between capecitabine and taxanes (contd) • Clinical studies: -The combination of capecitabine/docetaxel was found to be active in resistant human malignancies(Nadella P et al. J Clin Oncol 20:2616-23, 2002)and was found superior to docetaxel alone in patients with metastatic breast cancer(O`Shaughnessy J et al. J Clin Oncol 20:2812-23, 2002). -The combination of capecitabine plus paclitaxel was found highly active combination in metastatic breast cancer (Gradishar WJ et al. J Clin Oncol 22: 2321-7, 2004; Batista N et al. Br J Cancer 90: 1740-6, 2004).

  40. Possible interaction between docetaxel and gemcitabine Leu KM et al. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol 22: 1706-12, 2004 • 43% response rate among 35 pts with bone and soft tissue sarcomas (who had previously received doxorubicin and/or ifosfamide, or were pts in whom this combination was preferred for medical reasons). • “The reported response rates of single agent gemcitabine in pts with sarcomas= 3%, 3%, 5.5%, 11%, and 18%; The reported response rates of single agent docetaxel in pts with sarcomas= 0%, 6%, 15%, 17% and 18%. • Significant in-vitro activity in cell lines.

  41. Interaction (due to absorption) between cyclosporin and taxanes given by oral administration • The low bioavailability of taxanes after oral administration is at least in part due to their high affinity for the multidrug efflux pump P-glycoprotein (P-gp). P-gp in the GIT mucosa limits the absorption of the orally administered taxanes. • Cyclosporine A is an inhibitor of the P-gp pump, and enhances the bioavailability of oral docetaxel. (Malingre MM et al. J Clin Oncol 19: 1160-6, 2001) or oral paclitaxel (Kruijtzer CMF et al.J Clin Oncol 20: 4508-16, 2002). (In addition,cyclosporine is a substrate to P450 isoenzymes,which in the liver are responsible for the first pass elimination of taxanes, and therefore, contribute to the low bioavailability).

  42. Possible synergism between cyclo-oxygenase-2 (COX-2) inhibitors and paclitaxel • COX-2 is activated during inflammation and carcinogenesis and is overexpressed in several tumors. This enzyme catalyzes the synthesis of prostaglandins (PGs)(from arachydonic acid). PGs can enhance tumor growth and metastasis by stimulating angiogenesis and invasiveness, and inhibit apoptosis. • Paclitaxel and other microtubule-interfering agents induce COX-2 and PGs biosynthesis, thus theoretically reducing its own cytotoxic effect. • Celecoxib (a selected COX-2 inhibitor) enhanced the response to preoperative paclitaxel and carboplatin (compared to historical controls in early non small cell lung cancer. Altorki NK et al. J Clin Oncol 21: 2645-50, 2003 Dmitrovsky E. J Clin Oncol 21: 2631-2, 2003 (Editorial)

  43. Paclitaxel/warfarin Thompson ME and Highley MS. Ann Oncol 14: 500 (letter) • A case report of a patient in whom INR was increased during the first cycle of chemotherapy. • “The early increase in the INR suggests that displacement of warfarin from protein binding sites by paclitaxel is the most important mechanism for this apparent interaction”.

  44. Interactions with vinca alkaloids • drugs that interfere with cytochrome P-450…. • vinca alkaloides and phenytoin…. • Vincristine/methotrexate….

  45. Vinca Alkaoids and drugs that interfere with cytochrome P-450 CYP3A • Liver Cytochrome P-450 is involved in vinca alkaloids metabolism. • Therefore, potential interference is possible with inhibitors of CYP….Chan JD. Pharmacotherapy 18: 1304-7, 1998 (review):(cyclosporine, ketoconazole & others can lead to severe vincristine toxicity) And with drugs which cause induction of cytochrome P-450…...Vecht CJ. Lancet Neurol 2: 404-9, 2003 (review): (interactions with antiepileptic drugs can cause insufficient tumor and seizure control)., Villikka K et al. Clin Pharmacol Ther 66: 589-93, 1999 (CYTP3A4-inducing antiepileptics increase the clearance of vincristine).

  46. Vinca alkaloids and Phenytoin • See last slide…. In addition: • Treatment with vincristine or vinblastine can cause reduced phenytoin levels (and induce seizures). Mechanism? Vecht CJ. Lancet Neurol 2: 404-9, 2003 (review): “interactions with antiepileptic drugs can cause insufficient tumor and seizure control” See also:“Antiepileptic drugs and cytotoxic drugs”.

  47. Vincristine & Methotrexate Vincristine increases, in-vitro, accumulation of methotrexate in tumor cells (vinca-alkaloid induced blockade of drug efflux). In-vivo…?

  48. Interactions with estramustine phosphate • Food & calcium antacids…. • Taxotere: see taxanes….

  49. Estramustine phosphate (EP) &food & calcium antacids (interaction due to impaired absorption) Coadministration of food or dairy products impairs the absorption of EP. Calcium rich foods lead to formation of poorly absorbable calcium complex. Therefore, fasting and avoidance of calcium-rich foods and calcium antacids is recommended before oral EP administration.

  50. Interactions with etoposide • Cisplatin: see cisplatin…. • Drugs that affect cytochrome P-450 activity….

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