Long-term outcome of everolimus treatment in transplant patients

Abstract

Abstract:The authors review the use of everolimus in long-term studies both in renal and heart transplantation. The pharmacokinetic and pharmacodynamic differences between everolimus and its parent drug, sirolimus are discussed. The improved pharmacokinetic, in particular the improved bioavailability, the reduced half-time and the reduced binding to plasma protein makes everolimus the first choice among the proliferation signal inhibitors. Everolimus is given in almost all studies in association with cyclosporine, but fixed doses of this drug can cause nephrotoxicity. The first studies used everolimus and CsA in fixed doses, but later studies with reduced CsA doses revealed which revealed improved outcomes. Finally, therapeutic drug monitoring became the better choice for both drugs. Recently very high everolimus exposure allowed the use of very low CsA exposure with improvement of the worse side effects linked to the CsA standard dose. The Zeus study revealed a complete and safe CsA withdrawal, thanks to everolimus and mycophenolic acid. In heart transplantation, everolimus resulted in improved outcomes with respect to antiproliferative drugs such as mycophenolic acid and azathioprine. Along with antirejection properties, everolimus provided evidence for antiproliferative effects on several cells. This resulted in fewer viral infections (mainly CMV), anti-atherosclerotic properties (mainly important in heart transplantation, and antineoplastic effect. The latter activity resulted in lower cancer incidence in transplant patients treated by everolimus. An important piece of evidence for this activity is documented by the use of everolimus in the treatment of some cancers, including renal cancer, neuroendocrine cancers and hepatocellular cancers, also outside the field of transplantation.

Dose‐Dependent Acute Effects of Everolimus Administration on Immunological, Neuroendocrine and Psychological Parameters in Healthy Men

“…5 Our data revealed that the mean EVR trough levels of the medium-dose and high-dose groups obtained 12 hours after third but right before the last EVR administration were above the therapeutic threshold of 3 ng/mL and, therefore, comparable to therapeutic treatments. 2,5 Although EVR has been systemically washed out since study day 8, the observed anti-proliferative effects even persist 5 days after the last EVR administration in the medium-dose and high-dose groups, whereas for IL-10 suppression this was just the case in the highdose group. These findings suggest that higher doses of EVR induce residual immunosuppressive effects even when the drug is completely metabolized.…”

“…2,4 So far, EVR is the only clinically used mTOR inhibitor approved by the US Food and Drug Administration (FDA) for the oral administration and treatment of malignancies, including breast carcinoma, gastrointestinal tract-derived neuroendocrine tumors, renal cell carcinoma, and to prevent allograft rejection after heart, kidney, and liver transplantations. 1,2,5 Pharmacokinetic studies with transplant recipients obtaining EVR either with 0.75 mg/dose or 1.5 mg/dose twice a day combined with cyclosporin revealed maximal blood concentration of 11.1 ± 4.6 µg/L and 20.3 ± 8.0 µg/L, respectively, after 1 to 2 hours. 6,7 The elimination half-life amounts for 18-32 hours and steady-state is achieved between 4 and 7 days.…”

Worsening pneumonitis due to a pharmacokinetic drug-drug interaction between everolimus and voriconazole in a renal transplant patient

“…The decrease in everolimus dosage the day of introduction of voriconazole could not prevent the important increase in everolimus concentration and could have been accountable for the worsening of the patient's pulmonary symptoms. The estimated elimination half‐life of everolimus was twice higher the average reported value as the consequence of high voriconazole concentration and inhibitory effect on intestinal and hepatic CYP3A . As previously described with azole agents, this interaction is most likely a consequence of CYP3A4 inhibition .…”

The role of everolimus in liver transplantation

“…Everolimus is a 40-O-(2-hydroxyethyl) derivative,54 which was developed to improve the pharmacokinetic profile of sirolimus. The hydroxyethyl group provides a pharmacokinetic advantage, conferring faster absorption and a shorter half-life than sirolimus 55–57. Unlike sirolimus, no loading dose is required for everolimus, and the twice-daily dosing schedule allows better dose adjustments 57…”