Simvastatin 4- Imatinib

O Brien SG et al (2003) Effects of imatinib mesylate (STI571, glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer 89 1855-1859... 

ATORVASTATIN, SIMVASTATIN IMATINIB Imatinib may t atorvastatin and simvastatin levels Imatinib inhibits CYP3A4-mediated metabolism of simvastatin Monitor LFTs, U Es and CK closely... 

E Itraconazole. Imatinib is primarily metabolized by the CYP3A4 hepatic enzyme system. Drugs that may inhibit this enzyme (such as ketoconazole, itraconazole, erythromycin, clarithromycin, etc.) may impair clearance of imatinib and result in increased toxicity. Imatinib itself is also a fairly potent inhibitor of the CYP3A4 enzyme and may result in toxicity due to other drugs that are substrates for this enzyme (such as simvastatin, warfarin, benzodiazepines, etc.). The other medications iisted are uniikeiy to affect the function of 0 P3A4 or interact adversely with imatinib. 

Clinically important, potentially hazardous interactions with alprazolam, aprepitant, astemizole, atorvastatin, benzodiazepines, carbamazepine, chlordiazepoxide, cilostazol, clonazepam, clorazepate, colchicine, conivaptan, cyclosporine, dabigatran, dasatinib, diazepam, digoxin, dihydroergotamine, disopyramide, ergot alkaloids, fesoterodine, fluoxetine, flurazepam, fluvastatin, HMG-CoA reductase inhibitors, imatinib, ixabepilone, lapatinib, lopinavir, lorazepam, lovastatin, methylprednisolone, methysergide, midazolam, nilotinib, oxazepam, paroxetine, pimozide, pravastatin, prednisone, quazepam, repaglinide, rimonabant, rivaroxaban, sertraline, silodosin, simvastatin, solifenacin, temazepam, temsirolimus, tolvaptan, trabectedin, triazolam, warfarin, zidovudine... 

Clinically important, potentially hazardous interactions with amiloride, aminoglycosides, amphotericin B, ampicillin, anisindione, anticoagulants, armodafinil, atorvastatin, azathioprine, azithromycin, bacampicillin, basiliximab, bezafibrate, bosentan, bupropion, carbenicillin, caspofungin, cholestyramine, clarithromycin, cloxacillin, co-trimoxazole, corticosteroids, cyclophosphamide, daclizumab, danazol, dicloxacillin, dicumarol, digoxin, diltiazem, disulfiram, echinacea, erythromycin, ethotoin, etoposide, ezetimibe, flunisolide, fluoxymesterone, fluvastatin, foscarnet, fosphenytoin, gemfibrozil, hemophilus B vaccine, HMG-CoA reductase inhibitors, imatinib, imipenem/cilastatin, influenza vaccines, ketoconazole, lanreotide, lopinavir, lovastatin, mephenytoin, methicillin, methoxsalen, methylphenidate, methylprednisolone, methyltestosterone, mezlocillin, mizolastine, mycophenolate, nafcillin, nisoldipine, NSAIDs, orlistat, oxacillin, penicillins, phellodendron, phenytoin, pravastatin, prednisolone, prednisone, pristinamycin, ranolazine, red rice yeast, rifabutin, rifampin, rifapentine, ritonavir, rosuvastatin, simvastatin, sirolimus, spironolactone, St John s wort, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfonamides, tacrolimus, telithromycin, tenoxicam, testosterone, ticarcillin, tolvaptan, trabectedin, triamterene, troleandomycin, ursodeoxycholic acid, vaccines, vecuronium, warfarin, zofenopril... 

CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other CYPs play a minor role in imatinib s metabolisrrL Imatinib increased the peak plasma concentration andAUC o/simvastatin by 2 and 3.5 times, respectively, and coadministration with rifampin, an inducer of CYP3A4, reduces plasma imatinib AUC by -70%. Elimination of imatinib occurs predominantly in the feces, mostly as metabolites. 

Imatinib raises simvastatin serum levels, increasing the risk of toxicity. It seems likely that iovastatin and possibiy atorvastatin may also be similarly affected. 

As a general rule, any patient given imatinib with atorvastatin, lovasta-tin or simvastatin should be told to report any signs of myopathy and possible rhabdomyolysis (i.e. otherwise unexplained muscle pain, tenderness or weakness or dark coloured urine). If myopathy does occur, the statin should be stopped immediately. See also muscle toxicity , (p.l086), for further guidance on monitoring, and risk factors for muscle toxicity. 

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