Methods of treating cyp2d6 alternative metabolizers

Abstract

The invention provides various methods comprising the administration of a CYP2D6 bioactive drug covalently bound to a water-soluble oligomer. Metabolism of CYP2D6 bioactive drug conjugates is diverted from CYP2D6 to alternative pathways, and the conjugates may therefore be utilized to alleviate the problems associated with interpopulation variation resulting from the genetic polymorphism in the CYP2D6 gene.

1 . A method of treating a CYP2D6 alternative metabolizer having a disease treatable with a CYP2D6 bioactive drug, the method comprising administering to the CYP2D6 alternative metabolizer an effective amount of the drug covalently bound to a water-soluble oligomer. 
     
     
         2 . The method of  claim 1 , wherein the water-soluble oligomer is a polyethylene glycol (PEG) moiety. 
     
     
         3 . The method of  claim 1 , wherein the alternative metabolizer is selected from a poor metabolizer, an intermediate metabolizer, and an ultrarapid metabolizer. 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the drug covalently bound to a water-soluble oligomer is selected from a drug metabolized by CYP3A4, a drug that is a substrate of CYP2D6, a drug that is an inhibitor of CYP2D6, and a drug that is an inducer of CYP2D6. 
     
     
         7 . The method of  claim 2 , wherein the PEG moiety comprises 2-10 polyethylene glycol monomers. 
     
     
         8 . The method of  claim 7 , wherein the PEG moiety comprises 5-8 polyethylene glycol monomers. 
     
     
         9 . The method of  claim 7 , wherein the PEG moiety comprises 5-6 polyethylene glycol monomers. 
     
     
         10 . The method of  claim 7 , wherein the PEG moiety comprises 7-8 polyethylene glycol monomers. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the drug is a prodrug. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the drug is diphenhydramine. 
     
     
         16 . The method of  claim 1 , wherein the drug is hydroxyzine. 
     
     
         17 . A method of modulating the efficacy of a CYP2D6 bioactive drug in a CYP2D6 alternative metabolizer, the method comprising administering to the CYP2D6 alternative metabolizer an effective amount of the drug covalently bound to a water-soluble oligomer. 
     
     
         18 . The method of  claim 17 , wherein the water-soluble oligomer is a polyethylene glycol (PEG) moiety. 
     
     
         19 . The method of  claim 17 , wherein the PEG moiety comprises 2-10 polyethylene glycol monomers. 
     
     
         20 . The method of  claim 19 , wherein the PEG moiety comprises 5-8 polyethylene glycol monomers. 
     
     
         21 . The method of  claim 19 , wherein the PEG moiety comprises 5-6 polyethylene glycol monomers. 
     
     
         22 . The method of  claim 19 , wherein the PEG moiety comprises 7-8 polyethylene glycol monomers. 
     
     
         23 . The method of  claim 17 , wherein the alternative metabolizer is selected from a poor metabolizer, an intermediate metabolizer, and an ultrarapid metabolizer. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . A method of reducing drug-drug interactions in a CYP2D6 intermediate, extensive, or ultrarapid metabolizer, the method comprising co-administering to the metabolizer an effective amount of a CYP2D6 inhibiting drug with an effective amount of a CYP2D6 bioactive drug covalently bound to a water-soluble oligomer. 
     
     
         33 . The method of  claim 32 , wherein the water-soluble oligomer is a polyethylene glycol (PEG) moiety. 
     
     
         34 . The method of  claim 32 , wherein the PEG moiety comprises 2-10 polyethylene glycol monomers. 
     
     
         35 . The method of  claim 32 , wherein the PEG moiety comprises 5-8 polyethylene glycol monomers. 
     
     
         36 . The method of  claim 32 , wherein the PEG moiety comprises 5-6 polyethylene glycol monomers. 
     
     
         37 . The method of  claim 32 , wherein the PEG moiety comprises 7-8 polyethylene glycol monomers. 
     
     
         38 . (canceled) 
     
     
         39 . A compound comprising the formula D-X-POLY, wherein POLY is a water-soluble oligomer, X is a spacer moiety, and D is a CYP2D6 bioactive drug, provided that D is not a nucleotide, nucleoside, antihistamine, oxymorphone, platinum coordination complex based drugs, steroid, fluoroquinolone, retinoid, phenothiazine, benzodiazepine, galactogugues, thiazide, amlodipine, nifedipine, nimodipine, 5 hydroxytryptophan, nevirapine, amifostine, amiodarone, aminocaproic acid, aminohippurate sodium, aminoglutethimide, aminolevulinic acid, aminosalicylic acid, amsacrine, anagrelide, anastrozole, asparaginase, anthracyclines, bexarotene, bicalutamide, bleomycin, buserelin, busulfan, cabergoline, capecitabine, carboplatin, carmustine, chlorambucin, cilastatin sodium, cladribine, clodronate, cyclophosphamide, cyproterone, cytarabine, camptothecins, dacarbazine, dactinomycin, daunorubicin, deferoxamine, diclofenac, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, exemestane, fexofenadine, fludarabine, fluoxymesterone, flutamide, gemcitabine, epinephrine, L-Dopa, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, itraconazole, goserelin, letrozole, leucovorin, levamisole, lisinopril, lovothyroxine sodium, lomustine, mechlorethamine, melphalan, mercaptopurine, metaraminol bitartrate, methotrexate, metoclopramide, mexiletine, mitomycin, mitotane, mitoxantrone, nicotine, nilutamide, octreotide, pamidronate, pentostatin, pilcamycin, porfimer, procarbazine, prochlorperazine, ondansetron, raltitrexed, sirolimus, streptozocin, tacrolimus, tamoxifen, temozolomide, teniposide, tetrahydrocannabinol, thalidomide, thiotepa, topotecan, tretinoin, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, dolasetron, granisetron; formoterol, leuprolide, amphotericin B, podophylotoxins, nucleoside antivirals, aroyl hydrazones or sumatriptan. 
     
     
         40 . A compound of  claim 39 , wherein POLY is a polyethylene glycol (PEG) moiety. 
     
     
         41 . A compound of  claim 40 , wherein the PEG moiety comprises 2-10 polyethylene glycol monomers. 
     
     
         42 . The compound of  claim 40 , wherein the PEG moiety comprises 5-6 polyethylene glycol monomers. 
     
     
         43 . The compound of  claim 40 , wherein the PEG moiety comprises 7-8 polyethylene glycol monomers. 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . In a method of treating one or more diseases in a CYP2D6 intermediate, extensive, or ultrarapid metabolizer with a CYP2D6 bioactive drug and a CYP2D6 inhibiting drug comprising co-administering to the CYP2D6 intermediate, extensive, or ultrarapid metabolizer a CYP2D6 bioactive drug and a CYP2D6 inhibiting drug, the improvement comprising co-administering a therapeutically effective amount of the bioactive drug with a therapeutically effective amount of the inhibiting drug covalently bound to a polyethylene glycol (PEG) moiety. 
     
     
         51 . (canceled) 
     
     
         52 . The method of  claim 50 , wherein the PEG moiety comprises 2-10 polyethylene glycol monomers. 
     
     
         53 . The method of  claim 50 , wherein the PEG moiety comprises 5-8 polyethylene glycol monomers. 
     
     
         54 . The method of  claim 50 , wherein the PEG moiety comprises 5-6 polyethylene glycol monomers. 
     
     
         55 . The method of  claim 50 , wherein the PEG moiety comprises 7-8 polyethylene glycol monomers.