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הכנה לבחינות התמחות באונקולוגיה PowerPoint PPT Presentation

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הכנה לבחינות התמחות באונקולוגיה. טיפול תרופתי- תרופות ציטוטוקסיות: השפעות גומלין בין תרופתיות ובין תרופות לקרינה ערך: פרופ’ נ. חיים , יולי 2003, עודכן-ינואר 2004 כתובת לשאלות והערות : [email protected] Possible mechanisms of drug interactions. Synergism antagonism modulation

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: . , 2003, - 2004


[email protected]

Possible mechanisms of drug interactions

  • Synergism

  • antagonism

  • modulation

  • pharmacokinetic

  • metabolic

  • due to protein binding

  • Interaction due to drug absorption

  • pharmacodynamic: known or unknown reason

  • interaction due to common toxicity

  • interaction due to incompatibility in solution

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Interactions with 5FU & 5FU prodrugs

  • Cisplatin.

  • Interferons.

  • Lecovorin (l isomer).

  • DPD inhibitors

  • Methotrexate.

  • PALA.

  • Allopurinol.

  • Wafarin (coumadin).

  • Sorivudine and oral 5FU prodrugs.

  • Radiation therapy.

Synergism between cisplatin and 5FU

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

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

Modulation of 5FU action by leucovorin

Leucovorin stabilizes the

FdUdMP-TS-folate ternary complex

(a stable covalent complex with TS).

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).

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 FUMPwith enhanced FUTP incorporation into RNA.

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.

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.

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)

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.

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

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.

Interactions with methotrexate: antagonism with leucovorin

Leucovorin (tetrahydrofolate) is antagonist of methotrexate

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.

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).

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.

Interactions with gemcitabine

  • Cisplatin.

  • Radiation therapy.

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.

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.

Interactions with cisplatin/carboplatin

  • Etoposide.

  • Gemcitabine: see gemcitabine.

  • 5FU: see 5FU.

  • Paclitaxel: see taxanes.

  • drugs eliminated through kidneys.

  • Trastuzumab (Herceptin).

  • Radiation therapy.

Interactions between cisplatin and etoposide

Synergistic action.frequently used in combination.

Possible pharmacokinetic interactions of cisplatin with drugs eliminated through kidneys

  • Delayed excretion of methotrexate, bleomycin, ifosfamide (when given following or with cisplatin)

Interaction between cisplatin & herceptin

  • Herceptin was found to be in-vitro synergistic with cisplatin.

  • The combination of herceptin and cisplatin is clinically active.

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.

Interaction with taxanes

  • Paclitaxel/doxorubicin.

  • Inducers of CYP450.

  • Inhibitors of CYP450.

  • Paclitaxel/cisplatin.

  • Paclitaxel/carboplatin.

  • Taxol/herceptin

  • Docetaxel/estramustine phosphate

  • Docetaxel/capecitabine.

  • Taxanes (given PO)/cyclosporine.

  • Possible synergism between paclitaxel and cyclo-oxygenase-2 (COX-2) inhibitors

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

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

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)

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)

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).

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

Pharmacodynamic interaction of unknown reason -Taxol/Herceptin & cardiac dysfunction

Seidman A et al. J Clin Oncol 20: 1215-21, 2002

  • 1219 phase II&III.

  • Rate of cardiac dysfunction:






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

Interaction between capecitabine and docetaxel

  • Preclinical synergy: In human xenografts paclitaxel and docetaxel have been demonstrated to induce thymidine phosphorylase activity, (which may increase the metabolic activation of capecitabine) (Sarvada N et al. Clin Cancer Res 4: 1013-19, 1998).

  • 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).

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).

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 yhe 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. This might reduce the efficacy of paclitaxel.


Possible synergism between cyclo-oxygenase-2 (COX-2) inhibitors and paclitaxel (Contd.)

  • 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. The abrogated the increase in PGs levels in primary tumors seen after paclitaxel/carboplatin.

    Altorki NK et al. J Clin Oncol 21: 2645-50, 2003

    Dmitrovsky E. J Clin Oncol 21: 2631-2, 2003 (Editorial)

Interactions with vinca alkaloids

  • drugs that interfere with cytochrome P-450.

  • vinca alkaloides and phenytoin.

  • Vincristine/methotrexate.

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).

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.

Vincristine & Methotrexate

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

Interactions with estramustine phosphate

  • Food & calcium antacids.

  • Taxotere: see taxanes.

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.

Interactions with etoposide

  • Cisplatin: see cisplatin.

  • Drugs that affect cytochrome P-450 activity.

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

Interactions with doxorubicin

  • Paclitaxel: see taxanes.

  • Dexrazoxane: see chemotherapy protectants.

Interaction with camptothecin analogs

  • Inducers & inhibitors of CYP450.

  • Irinotecan and ketoconazole.

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

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

Interaction with alkylating agents

  • Cyclophosphamide & drugs affecting Cytochrome P-450.

  • Procarbazine.

  • Cyclophosphamide/ifosphamide & mesna: see chemotherapy protectants

  • Amifostine: see chemotherapy protectants

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).

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

Interaction between cytotoxic drugs and chemotherapy protectants

  • Amiphostine & alkylating agents.

  • Mesna & ifosfamide/cyclophosphamide.

  • Dexrazoxane & doxorubicin.


Interaction between cytotoxic drugs & radiation therapy

  • 5FU: see 5FU.

  • Gemcitabine: see gemcitabine.

  • Platinum analogs: see cisplatin.

  • Radiation recall reactions.

Interaction between cytotoxic drugs & radiation therapy: Radiation recall reactions induced by cytotoxic drugs

  • Develop in patients with prior exposure to radiotherapy and subsequent treatment with a precipitating agent; Occur in the field of prior irradiation; Radiation toxicity may not have been previously observed.

  • Dermatitis, pneumonitis, mucositis.

  • Dactinomycin, bleomycin, doxorubicin, etoposide, paclitaxel, gemcitabine

Nephrotoxic drugs & nephrotoxicity of cytotoxic drugs

  • ., see also methotrexate.


Nephrotoxic drugs & nephrotoxicity of cytotoxic drugs

  • Increased risk of nephrotoxicity when Streptozotocin(Streptozocin), cisplatin or high-dose methotrexate are given with other nephrotoxic drugs.

Pharmacodynamic interaction due to reversion of drug resistance

  • Reversion of MDR (experimental).

  • Cyclosporin A & oral Paclitaxel.

Reversion of MDR

  • MDR can be reversed experimentally by calcium-channel blockers, cyclosporine.

Pharmacodynamic & metabolic interaction: Cyclosporin A & oral Paclitaxel

  • Cyclosporin A (CsA) acts as a P-glycoprotein (P-gp) blocker (=pharmacodynamic interaction) and CYP-3A blocker (=metabolic interaction)

  • Co-administration of CsA resulted in an 8-fold exposure of oral paclitaxel (in patients with advanced gastric cancer).

    Kruijtzer CM et al. Ann Oncol 14: 197-204, 2003

Antiepileptic drugs and cytotoxic drugs

  • Antiepileptic drugs as inducers of cytochrome P-450.see previous slides.

  • Decreased phenytoin levels in pts treated with vincristine/vinblastine: see vinca alkaloids

  • Decreased phenytoin levels with other drugs/combinations

Decreased phenytoin levels with cytotoxic drugs/combinations (other than vinca)

  • Grossman SA et al. Am J Med 87: 505-10 :

    cisplatin & carmustine (BCNU)

  • Bollini P et al. Epilepsia 24: 75-8, 1983 (case report):

    carmustine, vinblastine, methotrexate combination

  • Sylvester RK et al. Ther Drug Monit 6: 302-5, 1984 (case report):

    cisplatin, vinblastine, bleomycin combination (impaired bioavailability)

Interaction due to incompatibility in solution

  • .

Interaction due to incompatibility in solution

  • cisplatin & mesna

  • cisplatin & glucose

  • carboplatin & NS solution

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