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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 אפריל 2006 כתובת לשאלות והערות: n_haim@rambam.health.gov.il. Types of drug-drug interactions.

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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 אפריל 2006 כתובת לשאלות והערות: n_haim@rambam.health.gov.il

  2. Types of drug-drug interactions • Pharmacokinetics (as a result of absorption, distribution, metabolism, and elimination). • Pharmacodynamics (when target organ or receptor site are affected) • Pharmaceutical (when 2 compounds interact because of they are incompatible either physically or chemically). (Vecht CJ et al. The Lancet Neurology 2: 404-9, 2003) (Beijnen JH and Schellens jan HM. The Lancet Oncology 5: 489-496, 2004) • Interactions can be wanted or unwanted. • Not all interactions are clinically relevant.

  3. Drug metabolizing enzymes • So called phase I drug metabolizing enzymes arepredominantly cytochrome P450-based). Members of the hepatic CYP system (CYP1, CYP2, and CYP3 sub-families of cytochrome P450) are the most relevant in terms of drug metabolism. The CYP system is the main pathway for biotransformation of drugs and endogenous substances. • The products of these reactions are usually more polar (and more readily excreted by the kidney). • The CYP 1,2,and3 families are involved in the metabolism of most drugs. The activity of these isoenzymes can either be induced or inhibited by exogenous substances. Inhibition can be expected when 2 drugs compete as substrate for the same coenzyme. see: Michael M. J Clin Oncol 23: 205-29, 2005; Vecht CJ et al. The Lancet Neurology 2: 404-9, 2003

  4. Drug interactions involving hepatic -mixed function oxidases(Cytohrome p-450) • Induction: barbiturates, phenytoin, (smoking and chronic alcohol ingestion). • Inhibition: cimetidine (more than ranitidine), erythromycin, ketoconazole fluconazole, corticosterids, testosterone

  5. Vecht CJ et al. Interactions between antiepileptic drugs and chemotherapeutic drugs. The Lancet Neurology 2: 404-9, 2003 Possible interactions include: • Reduced activity of the cytotoxic drug (i.e.-increase in the clearance of vincristine due to enzyme induction by phenobarbital, phenytoin, and carbamazepine. • Increased toxicity of the cytotoxic drug (i.e.-increase in AUC of etoposide due to inhibition of CYP isoenzymes by valproic acid (depalept) (which has no enzyme-inducing actions) or increased toxicity to procarbazine due to CYP induction by phenobarbital and increase in metabolic activation of procarbazine)…..contd

  6. Vecht CJ et al. Interactions between antiepileptic drugs and chemotherapeutic drugs. The Lancet Neurology 2: 404-9, 2003-contd • Reduced activity of antiepileptic drugs (i.e.-lower serum concentrations of phenytoin when given with cisplatin or vinca alkaloids; competitive binding?, protein displacement?, decreased absorption?). • Increased toxicity of antiepileptic drugs (i.e.-due inhibition of phenytoin metabolism by 5FU & analogs due to inhibition of CYP2C9).

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

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

  9. 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).

  10. Simon P et al. Clinical Pharmacology & Therapeutics 76: 45-54, 2004: “The coadministration of oxaliplatin in either standard or modified de Gramont regimen does not significantly affect the P/K of 5FU.

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

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

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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)]. Giunta G, Velluti F. J Pharm Technol 20: 77-9, 2004: • Subdural hematoma due to possible 5FU/warfarin interaction.

  18. 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)

  19. 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- GI bleeding) • Buyck HCE et al. Clinical Oncology 15: 1, 2003 (letter) (2 cases-GI bleeding) • Isaacs K and Haim N. J Chemother 17: 339-42, 2005 (1 case- hemorrhagic blisters & ecchymoses)

  20. Interaction between Capecitabine & Warfarin (Coumadin)-a P/K study • There is a significant P/K interaction between capecitabine and S-warfarin* (AUC increased by 57% and elimination half-life increased by 51%). *S-warfarin is one of the 2 enantiomers of warfarin (the other is R-warfarin). S-warfarin is the more active enantiomer, and is metabolized almost exclusively by CYP2C9. Camidge R et al. J Clin Oncol 21: 4719-25, 2005

  21. 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.

  22. 5FU/Gemcitabine …the combination of GEM/5FU is active but also toxic…….coadministration of gemcitabine with 5FU increased the systemic exposure to 5FU (Correale P et al. Eur J Cancer 39: 1547-51, 2003)…these 2 drugs may also interact at biochemical levels….

  23. 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

  24. Interaction between fluoropyrimidines and phenytoin Vecht CJ et al. Interactions between antiepileptic and chemotherapeutic drugs. The Lancet Neurology 2: 404-9, 2003-review: 5FU is an inhibitor of CYP2C9 and therefore, could potentiate the activity of antiepileptic drugs. Brickell K et al. Br J Cancer 18: 615-6, 2003: • 2 cases of clinical phenytoin toxicity occuring after starting treatment with 5FU/LCV and a third who developed clinical phenytoin toxicity after starting capecitabine. • Increased phenytoin plasma concentrations have been reported during concomitant use of capecitabine with phenytoin, (a cytochrome P450 2C9 substrate, suggesting a potential interaction)

  25. Interactions with methotrexate/pemetrexed • Leucovorin…. • Drugs that are cleared by tubular secretion…. • Potential interaction between methotrexate and omeprazole…. • Nephrotoxic drugs: vancomycin….cisplatin…. • Drugs that bind to protein…. • Vincristine: see vinca alkaloids…. • Pemetrexed & Folic acid/B12….

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

  27. 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.

  28. Potential interaction between methotrexate and omeprazole The renal hydrogen/potassium ATPase pump make the urine more acidic by secreting hydrogen ions into the renal tubule and reabsorbing potassium ions. Active tubular secretion of methotrexate requires the activity of this pump because methotrexate is excreted with hydrogen ions. Omeprazole can inhibit renal elimination of the hydrogen ion and block the active tubular secretion of methotrexate, which may result in potentially toxic concentrations of methotrexate (Reid T et al. Cancer Chemother Pharmacol 44: 82-9, 1993; Beorlegui B et al. Ann Pharmacother 34: 1024-7, 2000).

  29. 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 technecium 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).

  30. Methotrexate/cisplatin Haim N et al. Cancer Chemother Pharmacol 13: 223-5, 1984: Among 106 pts treated with conventional-dose MTX following prior therapy with cisplatin, 6 died with clinical manifestation of MTX toxicity. All of them had received MTX earlier without developing serious toxicity and at the time of last MTX had normal creatinine. Prior therapy with cisplatin may be responsible for this high incidence of MTX-related deaths.

  31. 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.

  32. Folic acid / B12 supplementation and toxicity of pemetrexed • Severe toxicities to MTA were linked to high blood levels of homocysteine and methylmalonic acid at study entry, suggesting that such toxicity and possibly some deaths may be related to reduced folic acid and B12 pools. • Folic acid and vitamin B12 supplementation causes significant reduction in plasma homocysteine concentrations and a significant reduction in the frequencies of severe hematolologic and non hematological complications.

  33. Interactions with gemcitabine • Cisplatin (& oxaliplatin)…. • Radiation therapy…. • Docetaxel: See: Taxanes….

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

  35. 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….

  36. Interactions with Fludarabine • Rituximab (mabthera)….

  37. Synergism between fludarabine and rituximab (mabthera) • Rituximab (R) biologic activity is associated with……and direct apoptosis. Fludarabine (F) also activate similar apoptotic pathways, providing rationale for combining fludarabine and rituximab. • Indeed, R+F demonstrate in-vitro synergistic antitumor activity (Alas S et al. Clin Cancer Res 7:709-23, 2001) and is active in low-grade follicular lymphoma (Czuczman MS et al. J Clin Oncol 23: 694-704, 2005).

  38. 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”…. • Temozolomide…. • Radiation therapy….. • Phenytoin….

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

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

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

  42. Interaction between cisplatin & temozolomide (TMZ) • TMZ produces methyl adducts at the O-6 position of guanine, which are removed by the repair enzyme AGAT. • In-vitro studies showed that cisplatin down-regulates the AGAT activity (and, therefore, to enhance the anti-tumoral activity of TMZ). Wang L et al. Carcinogenesis 10: 1681-4, 1989

  43. 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.

  44. Cisplatin/carboplatin & phenytoin • Lower concentrations of phenytoin when given with these drugs [Grossman SA et al. Am J Med 87: 505-10, 1989 (cisplatin); Dofferhoff HH et al. Am J Med 89: 247-8, 1989 (carboplatin)] • Mechanism- not clear…..

  45. 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…. • Antiepileptic drugs…. • Paclitaxel/glucocorticoids (?)….

  46. 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 • The effect of the vehicle of paclitaxel (cremophor EL = polyoxylated castor oil) should be also taken into account Millward MJ et al. Clin Cancer Res 4: 2321-29, 1998 (cremophor EL reduces doxorubicin clearance).

  47. 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 [(another explanation: in addition to the P/K interaction, paclitaxel may accelerate the metabolism of doxorubicin to doxorubicinol and other cardiotoxic metabolites in the cardiomyocytes (see:DeVita-7th edition, page 403)].

  48. 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)

  49. 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)

  50. 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) (see: DeVta-7th edition, page 403).

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