Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Abstract

Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced renal cell carcinoma and is being studied in patients with mantle cell lymphoma. Because temsirolimus and its primary metabolite, sirolimus, are metabolised by the cytochrome P450 3A4 pathway (CYP3A4), the potential exists for pharmacokinetic (PK) drug interactions with the numerous agents that modulate CYP3A4 isozyme activity. We investigated the effects of ketoconazole, a potent CYP3A4 inhibitor, on the PK profile of i.v. temsirolimus in healthy adults. Coadministration of 400 mg oral ketoconazole with 5 mg i.v. temsirolimus had no significant effect on temsirolimus maximum concentration (C max ) or area under the concentration curve (AUC). However, mean AUC increased 3.1-fold and AUC sum (sum of temsirolimus plus sirolimus AUCs) increased 2.3-fold compared with temsirolimus alone. A single 5-mg dose of temsirolimus with ketoconazole was well tolerated, and there were no unexpected safety results. Therefore, in cancer patients receiving 25 mg i.v. temsirolimus, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered.

Inhibitors of mTOR

“…P450-inducing anticonvulsant agents resulted in 73% and 50% lower C max and AUC values, respectively [45]. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered [46]. In vitro studies showed that temsirolimus and sirolimus inhibit the CYP2D6 isozyme (K i ϭ 1.5 and 5 M, respectively), indicating a potential for PK interaction with agents that are substrates of CYP2D6.…”

A single-dose placebo- and moxifloxacin-controlled study of the effects of temsirolimus on cardiac repolarization in healthy adults

“…First, potential effects of higher exposures on the QTc interval were not addressed and cannot be ruled out. Temsirolimus is a substrate of CYP3A4, and concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, has no effect on temsirolimus C max or AUC; however, a strong PK interaction leading to increased exposure of the primary metabolite sirolimus (C max , 2.2-fold; AUC, 3.1-fold) was observed [17]. In our study, PK/PD modeling indicated no relationship between temsirolimus or sirolimus exposure and prolongation of the QTc interval, but vigilance is still warranted and a temsirolimus dose reduction to 12.5 mg should be considered if administered with CYP3A4 inhibitors.…”

Temsirolimus for advanced renal cell carcinoma

“…The application of P450-inducing anticonvulsant agents resulted in lower C max and AUC values [46]. If a concomitant strong CYP 3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered [48]. Other studies demonstrated that temsirolimus inhibits the CYP 2D6 isoenzyme, indicating a potential for interactions with agents that are substrates of CYP 2D6 [49].…”