Ketoconazole modestly increases levels of donepezil. Eventhough this was not considered to be clinically significant,themanufacturers suggest that potent inhibitors of CYP3A4 willraise donepezil levels and inducers of CYP3A4 will lower donepezil levels. Galantamine levels are also increased by ketoconazole.
Clinical evidence,mechanism, importance and management
Donepezil 5mg daily was given to 18 healthy subjects with ketoconazole 200 mg daily, which is a specific and potent inhibitor of cytochrome P450 isoenzyme CYP3A4. After one week of concurrent use, maximum serum levels and AUC of donepezil were increased by less than 30%. Donepezil had no effect on pharmacokinetics of ketoconazole (See reference number 1). None of increases in donepezil levels were considered to be clinically relevant, and authors suggest that no dose modifications will be required with ketoconazole or other CYP3A4 inhibitors (See reference number 1). Despite this, UK manufacturer recommends that donepezil should be used with CYP3A4 inhibitors with care, and they specifically name itraconazole and erythromycin. Furthermore, both US and UK manufacturers suggest that CYP3A4 inducers (they name carbamazepine, dexamethasone, phenobarbital, phenytoin and rifampicin) may lower donepezil levels (See reference number 2,3). Be aware that a reduction in donepezil levels is possible with these drugs,but that a clinically significant interaction seems unlikely.
The manufacturers note that ketoconazole increased bioavailability of galantamine by 30%, probably as a result of CYP3A4 inhibition. They therefore predict that ketoconazole (and other potent CYP3A4 inhibitors such as ritonavir) may increase incidence of nausea and vomiting with galantamine, and suggest that, based on tolerability, a decrease in maintenance dose be considered (See reference number 4,5). Whether this is in fact necessary in practice remains to be established. Erythromycin,a moderate CYP3A4 inhibitor, only increased galantamine bioavailability by about 10%,(See reference number 4,5) and so a clinically significant interaction would not be expected.
Tiseo PJ,Perdomo CA, Friedhoff LT. Concurrent administration of donepezil HCl and ketoconazole: assessment of pharmacokinetic changes following single and multiple doses. Br J Clin Pharmacol (1998) 46 (Suppl 1), 30–34.
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