Itraconazole Atorvastatin

Itraconazole Alfentanil, alprazolam, astemizole, atorvastatin, buspirone, cisapride, cyclosporine, delavirdine, diazepam, digoxin, felodipine, indinavir, loratadine, lovastatin, midazolam, nisoldipine, phenytoin, quinidine, ritonavir, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, triazolam, verapamil, warfarin... 

Itraconazole increases serum concentrations of atorvastatin by inhibiting CYP3A4. In a randomized, double-blind, crossover study in 10 healthy volunteers, itraconazole 200 mg increased the AUC and half-life of atorvastatin 40 mg about three-fold, with a change in Cmax (33). The AUC of atorvastatin lactone was increased about 4-fold, and the Cmax and half-life were increased more than 2-fold. Itraconazole significantly reduced the Cmax and AUC of 2-hydroxyatorvastatin acid and 2-hydroxyator-vastatin lactone and increased the half-life of 2-hydroxyatorvastatin lactone. The concomitant use of itraconazole and other potent inhibitors of CYP3A4 with atorvastatin should therefore be avoided, or the dose of atorvastatin should be reduced accordingly. 

Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998 64(l) 58-65. 

The effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of atorvastatin, ceri-vastatin, and pravastatin have been evaluated in an open, randomized, crossover study in 18 healthy subjects who took single doses of atorvastatin 20 mg, cerivastatin 0.8 mg, or pravastatin 40 mg, with and without itraconazole 200 mg (72). Itraconazole markedly raised atorvastatin plasma concentrations (2.5-fold) and produced modest rises in the plasma concentrations of cerivastatin (1.3-fold) and pravastatin (1.5-fold). These results suggest that in patients taking itraconazole, cerivastatin or pravastatin may be preferable to atorvastatin. 

Physicians should check for lipid-lowering drugs before treating elderly individuals with itraconazole (73). Susceptibility to this interaction varies from statin to statin, in that simvastatin is more affected than pravastatin (74). Concomitant use of simvastatin with itraconazole should be avoided, and the same holds true for atorvastatin (75). In another study, the blood concentration of fluvastatin was not significantly increased, whereas that of lovastatin was (76). 

Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000 68(4) 391 100. 

CYP3A4 Inhibition Amiodarone, clarithromycin, erythromycin, cimetidine, cyclosporine, fluoxetine fluvoxamine, itraconazole, ketoconazole, nefazodone, verapamil, diltiazem HIV antivirals delaviridine, indanavire, nelfmavire, ritonavire, sequinavire Atorvastatin Lovastatin Simvastatin ... 

Abacavir Adinazolam 5-Aminosalicylic acid Atorvastatin Avitriptan Bromazepam Bumetanide Celecoxib CGP 43371 Clodronate Cyclosporin Danazol Didanosine Erythromycin Fexofenadine Furosemide Ganciclovir Halofantrine Inidnavir Itraconazole Levofloxacin Methotrexate Nifedipine Pravastatin Rifabutin Stavudine Tacrine... 

Itraconazole increases the risk of skeletal muscle toxicity of some statins by increasing their serum concentrations, but not all statins are equally affected. Concomitant use of atorvastatin, lovastatin, and simvastatin with itraconazole should be avoided or the doses should be reduced fluvastatin and pravastatin have much less potential than other statins for chnically significant interactions with itraconazole and other CYP3A4 inhibitors the effects of cerivastatin are intermediate. 

In a randomized, open, three-way, crossover study, 18 healthy subjects took single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without or with itraconazole 200 mg (111). Concomitant cerivastatin - - itraconazole and pravastatin -I- itraconazole produced small increases in AUC, Cmax, and half-Ufe (up to 51%, 25%, and 23% respectively). However, itraconazole markedly increased atorvastatin AUC (150%),... 

Itraconazole increases serum concentrations of atorvastatin by inhibiting CYP3A4. In a randomized, doubleblind, crossover study in 10 healthy volunteers. 

Clinically important, potentially hazardous interactions with astemizole, atorvastatin, cyclosporine, fluvastatin, glibenclamide, glyburide, itraconazole, ketoconazole, lovastatin, oral contraceptives, reboxetine, simvastatin, St John s wort,... 

Clinically important, potentially hazardous interactions with alfentanil, aminophylline, amisulpride, amoxicillin, ampicillin, anticonvulsants, astemizole, atorvastatin, benzodiazepines, bromocriptine, buprenorphine, bupropion, carbamazepine, cilostazol, ciprofloxacin, cisapride, clindamycin, colchicine, cyclosporine, dasatinib, digoxin, dihydroergotamine, diltiazem, disopyramide, enoxacin, eplerenone, ergotamine, eszopiclone, everolimus, fluconazole, fluoxetine, fluvastatin, gatifloxacin, HMG-CoA reductase inhibitors, imatinib, itraconazole, ketoconazole, lomefloxacin, lorazepam, lovastatin, methadone, methylprednisolone, methysergide, midazolam, mizolastine, moxifloxacin, nitrazepam, norfloxacin, ofloxacin, paroxetine, pimozide, pravastatin, quinolones, ranolazine, repaglinide, rupatadine, sertraline, sildenafil, simvastatin, sparfloxacin, sulpiride, tacrolimus, terfenadine, triazolam, troleandomycin, vardenafil, verapamil, vinblastine, warfarin, zaleplon, zolpidem, zuclopenthixol... 

Clinically important, potentially hazardous interactions with amlodipine, anisindione, anticoagulants, aprepitant, atorvastatin, barbiturates, benzodiazepines, butabarbital, carbamazepine, chlordiazepoxide, clarithromycin, clonazepam, dorazepate, corticosteroids, cyclosporine, dexamethasone, diazepam, dicumarol, erythromycin, ethotoin, felodipine, flurazepam, fluvastatin, fosphenytoin, isradipine, itraconazole, ketoconazole, lorazepam, lovastatin, mephenytoin, mephobarbital, midazolam, nicardipine, nifedipine, nimodipine, nisoldipine, oxazepam, pentobarbital, phenobarbital, pimozide, pravastatin, primidone, quazepam, rifampin, secobarbital, simvastatin, St John s wort, temazepam, warfarin... 

Clinically important, potentially hazardous interactions with abacavir, atorvastatin, bepridil, bupropion, carbamazepine, clarithromycin, cyclosporine, dexamethasone, digoxin, felodipine, fluticasone propionate, fosamprenavir, itraconazole, ketoconazole, lovastatin, methadone, midazolam, nicardipine, nifedipine, phenobarbital, phenytoin, rifabutin, simvastatin, sirolimus, St John s wort, systemic lidocaine, tacrolimus, tenofovir, trazodone, vinblastine, vincristine, voriconazole, warfarin, zidovudine... 

Figure 11.9 Different effects of itraconazole and obtained from the previous literature. The details cyclosporin A on the plasma AUC of pravastatin, are described in the Section 11.7.1. BA simvastatin, and atorvastatin [210, 221-224], bioavailability, Fa Fg fraction of dose absorbed The fold-increase in the plasma AUC of statins from the small intestine to the portal vein, Fh was expressed after coadministration of hepatic availability,...

Transporter efflux transporter effects predominant Examples Amiodarone Atorvastatin Azithromycin Carbamazepine Carvediioi Chlorpromazine Ciprofloxacin Cisapride Cyciosporine Danazoi Dapsone Diclofenac Diflunisal Digoxin Erythromycin Flurbiprofen Glipizide Glyburide Griseofulvin Ibuprofen Indinavir Indomethacin Itraconazole Ketoconazole Lansoprazole Lovastatin Mebendazole Naproxen Nelfinavir Ofloxacin Oxaprozin Phenazopyridine Phenytoin Piroxicam Raloxifene Ritonavir Saquinavir Saquinavir Sirolimus Sirolimus Spironolactone Spironolactone Tacrolimus Tacrolimus ... 

Ten healthy subjects were given itraconazole 200 mg daily for 5 days with a single 40-mg dose of atorvastatin on day 4. The itraconazole increased the AUC of atorvastatin acid and atorvastatin lactone fourfold and threefold, respectively, and increased their half-lives threefold and twofold, respectively. The AUC values of active and total HMG-CoA reductase inhibitors were increased 1.6- and 1.7-fold, respectively. In a similar study the same dose of itraconazole increased the AUC of atorvastatin by 2.5-fold and of atorvastatin lactone by about threefold. Another study has also shown that itraconazole raises atorvastatin levels. ... 

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