Tolterodine Ketoconazole

A4 inhibitors - Patients receiving cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole, itraconazole, and miconazole), or cyclosporine or vinblastine should not receive doses of tolterodine greater than 1 mg twice/day (greater than 2 mg/day for ER capsules). 

ANTIMUSCARINICS ANTIFUNGALS -ITRACONAZOLE, KETOCONAZOLE 1. i ketoconazole levels. 2. t darifenacin, solifenacin and tolterodine levels 1. 1 absorption 2. Inhibited metabolism 1. Watch for poor response to keto-conazole 2. Avoid co-administration of itraconazole, ketoconazole and these antimuscarinics. The US manufacturer of darifenacin recommends that its dose should not exceed 7.5 mg/day... 

Tolterodine is eliminated by two different oxidative metabolic pathways hydroxylation, catalysed by CYP2D6, and Z)-alkylation, catalysed by CYP3A. The pharmacokinetics and safety of tolterodine and its metabolites in the absence and presence of ketoconazole have been investigated in healthy volunteers with deficient CYP2D6 activity (poor metabolizers) (55). Clearance of tolterodine fell by 60% during co-administration of ketoconazole, resulting in a 2.1-fold increase in AUC. Thus, caution is needed when ketoconazole and other potent inhibitors of CYP3A are used concomitantly with tolterodine. 

Ketoconazole can increase tolterodine levels in those who are deficient in the cytochrome P450 isoenzyme CYP2D6 (poor metab-olisers). The manufacturers of tolterodine currently say that potent CYP3A4 inhibitors such as clarithromycin, erythromycin, itraconazole and ketoconazole, and protease inhibitors should be used with caution or avoided because of a risk of increased tolterodine effects. 

A study in 8 healthy subjects who were deficient in the cytochrome P450 isoenzyme CYP2D6 (poor metabolisers) found that after taking ketoconazole 200 mg daily for 4 days the clearance of a single 2-mg dose of tolterodine was reduc by 61% and its AUC was increased 2.5-fold. A subsequent multiple-dose study in 6 of the original subjects given tolterodine 1 mg twice daily (half the usual dose) found similar increased levels ketoconazole 200 mg once daily caused a 2.1-fold increase in tolterodine AUC, and a 2.2-fold increase in the AUC of the active moiety (unbound tolterodine plus metabolite). ... 

Although tolterodine is normally metabolised to its active metabolite by CYP2D6, in those with low levels of this isoenzyme (about 5 to 10% of the population), metabolism by CYP3A4, becomes more important. It should be noted that tolterodine levels are already higher in poor CYP2D6 metabolisers than extensive metabolisers but are likely to rise even further when a potent CYP3A4 inhibitor such as ketoconazole blocks this other route of metabolism. 

The UK manufacturers consider that this increase in levels represents a risk of overdose in poor CYP2D6 metabolisers. Consequently, they do not recommend the use of potent CYP3A4 inhibitors (they name clarithromycin, erythromycin, ketoconazole, and itraconazole, and protease inhibitors) with tolterodine in any patient (note that metaboliser status is rarely known). However, the US manufacturers recommend only that the dose of tolterodine be reduced to 1 mg twice daily in patients currently taking drugs that are potent inhibitors of CYP3A4, and this seems the more sensible advice. It may be prudent to assess experience of adverse effects in these patients, and to reduce the dose further or withdraw the drug if it is not tolerated. 

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