Correlation of Everolimus Exposure With Efficacy and Safety Outcomes: Results From a Multicenter Study in Renal Transplantation Using Reduced Csa Exposure

Abstract

Introduction: Everolimus (EVR), allows for reduction in CNI exposure with preserved renal function without loss of efficacy in renal transplant recipients (RTs). Data from earlier studies suggests that targeting EVR C0 levels to >3ng/mL may provide optimal benefits in RTs. This study explores the optimal EVR C0 level by correlating trough levels of EVR at 12 months (M) with efficacy and safety parameters. Methods: This 24M, randomized, multi-center, openlabel, non-inferiority study compared 2 target trough levels of EVR (C0 3-8ng/mL or C0 6-12ng/mL) with reduced CsA versus control group receiving enteric-coated mycophenolate sodium (MPA) 1.44g/day with standard CsA exposure. All RTs received basiliximab induction and steroids as per center practice. The objective of this post-hoc analysis was to correlate EVR C0 ranges with key efficacy and safety parameters including % of RTs with selected renal function events by 12M. Pooled analysis using the geometric mean of all measured EVR C0 levels up to the time of outcome or last study visit (12M) were used to correlate with key outcomes. Results: Donor and recipient characteristics were comparable between groups. Both EVR groups were statistically non-inferior to the MPA control group for the primary composite efficacy failure (treated biopsy proven acute rejection [BPAR], graft loss, death or loss to follow up) and the renal function safety endpoints at 12M. Mean CsA C0 at 12M were 55, 49 and 137 ng/mL for 3-8, 6-12ng/mL EVR and MPA groups respectively, reflecting a 60% reduction in CsA levels for both EVR groups. Mean EVR C0 at 12M were 5.2 and 7.9ng/mL for 3-8 and 6-12ng/ mL groups respectively. (Results listed in table). The probability of decreased glomerular filtration rate (GFR) correlates with CsA C0, but not with EVR C0 levels. Conclusions: EVR C0 range of 3-<8ng/ mL during the first 12M provided similar efficacy and renal function outcomes to MPA control. In addition, EVR C0 target of 3-<8ng/ml had less proteinuria and other adverse events compared to higher EVR C0 targets. Therefore, EVR C0 range of 3-<8ng/mL appears to be the optimal EVR C0 target range in de novo RTs receiving reduced exposure CsA. [Table] EVR C0 levels and efficacy and safety outcomes in patients

Efficiency of late conversion from mycophenolate mofetil to everolimus in kidney graft recipients with posttransplant malignancy

“…В отличие от исследований других авторов у наших пациентов функция почеч-ного трансплантата вне зависимости от ее исходного уровня снижалась, о чем свидетельствовал анализ ди-намики уровня Scr, который к моменту окончания на-блюдения оказался выше в сравнении с его исходным уровнем и составил 0,15 ± 0,09 и 0,13 ± 0,04 ммоль/л соответственно, p < 0,031. Оценить прогностическое значение протеинурии для исхода терапии ИПС у на-ших больных не представлялось возможным, так как только у 3 из 62 больных суточная протеинурия к на-чалу лечения превышала 0,3 г. Протеинурия в дина-мике в нашем наблюдении нарастала, что согласуется с данными литературы [34][35][36]. Средний показатель суточной экскреции белка с мочой повысился с 0,18 ± 0,25 до 0,75 ± 1,63 г, p < 0,011, в то время как число больных с протеинурией за время лечения возросло с 4,8 до 19,6%, причем почти у половины из них проте-инурия достигала субнефротического и нефротичес-кого уровня.…”

“…Другими препятствиями к более широ-кому использованию ИПС могут быть их побочные эффекты, такие как периферические отеки, язвен-ный стоматит, кожные реакции и артриты, пнев-мониты, миелопатии и др. нежелательные явления [22,[33][34][35][36]. Учитывая вышеизложенное, представ-ляло интерес оценить результаты применения эве-ролимуса у реципиентов почечного трансплантата с онкологическими осложнениями по материалам наблюдений одного центра.…”

Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation

“…Target everolimus concentrations of 3-8 ng/mL were defined, based on these studies, as therapeutic concentrations in combination with reduced calcineurin inhibitor exposure. 122 The mean dose required to achieve this concentration was 2.6 mg/day when everolimus was combined with cyclosporine 64 and 3.0-3.5 mg when combined with tacrolimus. 67,69 However, there is no target concentration defined when everolimus is combined with mycophenolate mofetil/mycophenolate sodium.…”

“…In this study, patients were randomized to receive initial everolimus doses of 0.75 mg twice daily adjusted to obtain an everolimus C min of 3-8 ng/mL or 1.5 mg twice daily adjusted to obtain an everolimus C min of 6-12 ng/mL. 122 Several class-related adverse events, including dyslipidemia, new-onset diabetes, wound healing complications, and proteinuria appear to be associated with the everolimus C min . The use of everolimus, regardless of dose or concentration, was associated with an increased risk of oral ulcers and peripheral edema.…”

“…Everolimus concentrations were not associated with impaired renal function. 122,123 On the other hand, the significant reduction in cyclosporine concentrations among patients receiving everolimus was associated with significant reductions in cyclosporine-related adverse events. Furthermore, even within the lower range of cyclosporine exposures obtained in patients receiving everolimus, there was an association between cyclosporine concentrations and impaired renal function.…”