Blood Concentrations of Everolimus Are Markedly Increased by Ketoconazole

Abstract

The authors sought to quantify the influence of the CYP3A and P-glycoprotein inhibitor ketoconazole on the pharmacokinetics of everolimus in healthy subjects. This was a 2-period, single-sequence, crossover study in 12 healthy subjects. In period 1, subjects received the reference treatment of a single 2-mg dose of everolimus. In period 2, they received the test treatment of ketoconazole 200 mg twice daily for a total of 8 days and a single dose of everolimus coadministered on the fourth day of ketoconazole therapy. The test/reference ratio and 90% confidence interval were derived for everolimus maximum concentration and area under the curve. During ketoconazole coadministration, everolimus maximum concentration increased 3.9-fold (90% confidence interval, 3.4-4.6) from 15 +/- 4 ng/mL to 59 +/- 13 ng/mL. Everolimus area under the curve increased 15.0-fold (90% confidence interval, 13.6-16.6) from 90 +/- 23 ng*h/mL to 1324 +/- 232 ng*h/mL. Everolimus half-life was prolonged by 1.9-fold from 30 +/- 4 hours to 56 +/- 5 hours. Everolimus did not appear to alter ketoconazole predose concentrations. Given the magnitude of this drug interaction, use of ketoconazole should be avoided if possible in everolimus-treated patients.

Disposition of everolimus in mdr1a−/1b− mice and after a pre-treatment of lapatinib in Swiss mice

“…When everolimus was coadministred with ketoconazole, a potent cytochrom 3A4 inhibitor, in 12 healthy volonteers, a 15-fold AUC 0→Tlast increase has been observed, as compared to everolimus group alone. Also, a 1.9-fold prolongation of elimination half-life (30 ± 4 vs 56 ± 5 h) was shown [12]. Verapamil is described like an important inhibitor of P-gp and less important inhibitor of cytochrom 3A while ketoconazole is both a potent inhibitor of P-gp and cytochrom 3A.…”

“…The CYP 3A represent almost 30% of the cytochromes in the liver and 70% of the cytochromes in the small intestine [10]. Many studies have demonstrated that inhibitors of cytochromes 3A are leading to an increase of AUC of drug substrates with a prolongation of half time elimination [11,12]. P-gp is part of a large family of efflux transporters which is expressed in the gonads, kidneys, biliary system, intestinal epithelium, brain capillaries and lymphocytes.…”

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

“…Orally administered sirolimus exhibits a substantial PK drug interaction with ketaconazole, resulting in increased whole blood exposure to sirolimus (Zimmerman, 2004). Oral structural analogues of sirolimus (tacrolimus and everolimus) are also CYP3A4 substrates and exhibit strong drug interactions with ketoconazole (Kovarik et al, 2005(Kovarik et al, , 2006El-Dahshan et al, 2006). This drug interaction study was conducted in healthy adults to assess the PK profile of a single i.v.…”

Everolimus Is a Potent Inducer of Erythroid Differentiation and γ-Globin Gene Expression in Human Erythroid Cells

“…Interestingly, steady-state serum levels reached by this compound in in vivo treated patients [40,41,42] are much higher than those demonstrated to be able to induce γ-globin gene expression in erythroid precursor cells from β-thalassaemia patients. Therefore, everolimus might be considered for pre-clinical trials to determine whether it has an effect on HbF production.…”