הכנה לבחינות התמחות באונקולוגיה

1. הכנה לבחינות התמחות באונקולוגיה טיפול תרופתי- תרופות ציטוטוקסיות: השפעות גומלין בין תרופתיות ובין תרופות לקרינה ערך: פרופ’ נ. חיים , יולי 2003 כתובת לשאלות והערות: n_haim@rambam.health.gov.il

2. Possible mechanisms of drug interactions • Synergism • antagonism • modulation • pharmacokinetic • metabolic • due to protein binding • pharmacodynamic: known or unknown reason • interaction due to common toxicity • “interaction” due to incompatibility in solution הערות: ראה שקופית הבאה...

3. 1. החלוקה הנ”ל שרירותית ובלתי שלמה. השפעת הגומלין היא בד”כ מורכבת, למשל, מטבולית ופרמקוקינטית, מטבולית וסינרגיסטית, מטבולית ואנטגוניסטית וכו'. • 2. יש להבדיל בין השפעות גומלין, שחשיבותן הקלינית מוכחת, כאלה שקיים ספק לגבי משמעותן הקלינית , והשפעות גומלין בין-תרופתיות, שהוכחו במערכות ניסיוניות בלבד. • 3. מצגת זאת מכילה דוגמאות מייצגות של השפעות גומלין, הקשורות לתרופות ציטוטוקסיות.

4. Interactions with 5FU • Cisplatin…. • Interferons…. • Lecovorin (l isomer)…. • DPD inhibitors • Methotrexate…. • PALA…. • Allopurinol…. • Wafarin (coumadin)…. • Radiation therapy….

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

6. 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

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

8. Modulation of 5FU by DPD inhibitors 1. Uracil (in UFT): inhibits DPD… 2. 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%). 3. 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).

9. 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.

10. 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.

11. 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.

12. Interaction between 5FU & Warfarin (Coumadin) • 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. • The etiology of such interaction is not clear (possible explanations: 5FU may impair vitamin K absorption…. interfere with warfarin degradation….). Masci G et al. J Clin Oncol 21:736-9,2003 Magagnoli M et al.Ann Oncol 14: 959-60,2003 (letter)

13. 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

14. 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….

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

16. 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.

17. 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).

18. 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.

19. Interactions with gemcitabine • Cisplatin…. • Radiation therapy….

20. 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.

21. 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….

22. Interactions with cisplatin/carboplatin • Etoposide…. • Gemcitabine: see gemcitabine…. • 5FU: see 5FU…. • Paclitaxel: see taxanes…. • drugs eliminated through kidneys…. • Trastuzumab (Herceptin)…. • Radiation therapy….

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

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

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

26. 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.

27. Interaction with taxanes • Paclitaxel/doxorubicin…. • Inducers of CYP450…. • Inhibitors of CYP450…. • Paclitaxel/cisplatin…. • Paclitaxel/carboplatin…. • Taxol/herceptin • Dcetaxel/estramustine phosphate

28. 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

29. Metabolic/pharmacokinetic interaction between paclitaxeland 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

30. 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)

31. 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)

32. 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).

33. 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

34. 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%

35. 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

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

37. 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).

38. 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”.

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

40. Interactions with estramustine phosphate • Food…. • Taxotere: see taxanes….

41. Estramustine phosphate (EP) &food • 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.

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

43. Interaction between etoposide and drugs that affect cytochrome P-450 activity • Because etoposide undergoes liver metabolism…. (see also taxanes)…. • Greater systemic clearance of etoposide (given in high-dose) in pts treated with anticonvulsants Rodman JH et al. J Clin Oncol 12: 2390-7, 1994

44. Interactions with doxorubicin • Paclitaxel: see taxanes…. • Dexrazoxane: see chemotherapy protectants….

45. Interaction with camptothecin analogs • Inducers & inhibitors of CYP450…. • Irinotecan and ketoconazole….

46. Metabolic/pharmacokinetic interaction between irinotecan/topotecan and drugs affecting Cytochrome P-450 metabolism Possible (theoretical) interaction as with taxanes or vinca alkaloids Kuhn JG. Oncology (Huntingt) 16: 33- 40, 2002 (influence of anticonvulsants) Haaz MC et al. Cancer Res 58:468-72,1998

47. Metabolic/pharmacokinetic interaction: Irinotecan & Ketoconazole • Irinotecan is a prodrug of SN-38. • It is converted by the cytochrome P-450 isozyme (CYP3A4) to several inactive metabolites.(This class ofenzymes, particularly the CYP3A4 isozyme, is responsible for the oxidation of more than 50% of drugs-resulting in more polar and usually inactive metabolites). • Ketoconazole, a CYP3A4 inhibitor, leads to significant increase formation of SN-38, and can potentially result in fatal outcomes. Kehrer DF et al. et al. J Clin Oncol 20: 3122-9, 2002

48. Interaction with alkylating agents • Cyclophosphamide & drugs affecting Cytochrome P-450…. • Procarbazine…. • Cyclophosphamide/ifosphamide & mesna: see chemotherapy protectants • Amifostine: see chemotherapy protectants

49. Cyclophosphamide & drugs that affect CYP450 enzyme activity Potential but of unknown clinical significance interaction with CYP450 enzyme activity inducers (e.g. barbiturates) or blockers (e.g. glucocorticoids).

50. Interactions with Procarbzine • CNS depressants: increased CNS effect due to MAO inhibition • Sympathomimetic drugs (e.g. isopreterenol, ephedrine): increased effect • hypertensive crisis (headache, tremor, palpitations): tricyclic antidepressants or tyramine-rich foods • Antabuse-like activity with GI toxicity,and headache: if concomitant alcohol