Ketoconazole Ciclosporin

CICLOSPORIN AZOLES - ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE t plasma concentrations of ciclosporin, with risk of nephrotoxicity, myelosuppression, neurotoxicity, excessive immunosuppression, with risk of infection and post-transplant lymphoproliferative disease Inhibition of CYP3A4-mediated metabolism of ciclosporin these inhibitors vary in potency. Ketoconazole and itraconazole are classified as potent inhibitors. Effect not clinically relevant with fluconazole Avoid co-administration with itraconazole or ketoconazole. Consider alternative azole but need to monitor plasma ciclosporin levels to prevent toxicity... 

Among the imidazole derivatives, numerous case reports or studies have shown that ketoconazole, fluconazole, and itraconazole can inhibit ciclosporin metabolism and increase blood ciclosporin concentrations (267). Ketoconazole, which is undoubtedly the most potent inhibitor, has been used to reduce the dose, and therefore the cost or adverse effects, of ciclosporin (268-270). There was also a beneficial effect on the rate of rejection or infection. In contrast, interactions with metronidazole and miconazole have only been described in isolated case histories (SEDA-19, 351) (5). 

The fact that ketoconazole inhibits cytochrome P450 accounts for some of its interactions. Ketoconazole increases ciclosporin concentrations, enhancing the risk of renal impairment, as shown by a fall in creatinine clearance (SED-12, 678) (6,13,25,36). 

The effect of ketoconazole in ciclosporin-treated kidney transplant recipients has been the subject of a prospective randomized study (37). In 51 ketoconazole-treated patients and 49 controls there was a similar frequency of acute rejection episodes. However, in the control group, rejection episodes were more recurrent, with a poorer response to treatment. Acute ciclosporin nephrotoxicity was more common in the ketoconazole group, but this was encountered more at induction and rapidly reversed on further reduction of the dose of ciclosporin. Chronic graft dysfunction was significantly less in... 

If erythromycin and ketoconazole, both CYP3A4 inhibitors, are taken in combination, there will be an even more dramatic effect on the metabolism of other drugs, such as terfenadine and astemizole, midazolam and triazolam, and ciclosporin. 

It is interesting to know which particular isoenzyme is responsible for the metabolism of drugs because by doing in vitro tests with human liver enzymes it is often possible to explain why and how some drugs interact. For example, ciclosporin is metabolised by CYP3A4, and we know that ri-fampicin (rifampin) is a potent inducer of this isoenzyme, whereas keto-conazole inhibits its activity, so that it comes as no surprise that rifampicin reduces the effects of ciclosporin and ketoconazole increases it. 

In vitro studies have shown that the cytochrome P450 isoenzyme CYP3A4 is the principal enzyme involved in the metabolism of zonisamide. Based on in vitro data, it is predicted that ketoconazole, ciclosporin, miconazole and fluconazole may cause a modest to minor decrease in the clearance of zonisamide. Conversely, itraconazole and triazolam are not predicted to have an effect. In vitro predictions do not always mirror what happens in clinical use, therefore, further study is needed. 

The evidence suggests that all the azole antifungals can raise ciclosporin levels to a greater or lesser degree. Ketoconazole may cause five- to tenfold rises, while itraconazole, fluconazole and voriconazole may cause two- to threefold rises. A case report suggests that intravenous miconazole interacts similarly and in theory, miconazole oral gel may also interact. Posaconazole may also modestly raise ciclosporin levels. Rhabdomyolysis has been reported with the combination of ciclosporin and itraconazole, but four of these cases were complicated by the presence of statins. 

Ketoconazole 200 mg daily caused a marked and rapid rise in the ciclosporin blood levels of36 renal transplant patients. On the basis of experience with previous patients, the ciclosporin dosage was reduced by 70% when ketoconazole was started, and after a year the dosage reduction was 85% (from 420 mg to 66 mg daily). Minimal nephrotoxicity was seen. " A study in children with nephrotic syndrome found the addition of ketoconazole allowed a ciclosporin dose reduction of approximately 37%. They also found that those in the ketoconazole treated group (153 patients) had a lower frequency of renal impairment, were more likely to be able to stop taking steroids and had a better chance of staying in remission than those not given ketoconazole (54 patients). ... 

Other reports " describe essentially similar rises in ciclosporin levels during the use of ketoconazole. The effects of ketoconazole on ciclosporin were found to be slightly increased (from 80 to 85%) when diltiazem was also given. Ketoconazole 2% cream has been found not interact with ciclosporin 1 mg/kg daily in the treatment of contact allergic dermatitis and the ciclosporin dosage does not need to be reduced. Impaired glucose tolerance has been attributed to the use of ketoconazole and ciclosporin in one patient. ... 

A clinical study in 23 healthy subjects found that while taking ketoconazole 200 mg daily for 10 days, the maximum serum levels and AUC of a single 5-mg dose of sirolimus were increased 4.3-fold and 10.9-fold, respectively. In a study in 6 kidney transplant patients, ciclosporin was stopped because of toxicity or rejection episodes and sirolimus was started. They were given a lower than recommended dose of sirolimus (250 to 500 micrograms daily) but were also given ketoconazole 100 to 200 mg daily, adjusted to maintain sirolimus levels within the therapeutic range. The serum creatinine of the patients improved and reduced from 230 micromol/L to 194 micromol/L. ... 

Especially the inhibition or induction of cytochrome P450 subtype 3A4 (CYP 3A4) is clinically relevant, because a variety of active substances and food substances (e.g. grapefruit juice) are able to affect this enzyme. Substances inhibiting CYP 3A4 include ciclosporin, dihydropyridines, verapamil, midazolam, paclitaxel, simvastatin, lovastatin, atorvastatin, cimetidine, erythromycin, troleandomycin, ketoconazole (and other azoles). Substances inducing CYP 3A4 include steroids, rifampicin, phenobarbital and St John s wort. 

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