Entry‐into‐human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients

Abstract

Aims To evaluate the tolerability of single oral SDZ RAD doses in stable renal transplant recipients and the pharmacokinetics of ascending SDZ RAD doses when coadministered with steady-state cyclosporin A microemulsion (Neoral). Methods This randomized, double-blind, placebo-controlled, sequential study involved 54 patients in six treatment groups; a different SDZ RAD dose (0.25, 0.75, 2.5, 7.5, 15, 25 mg ) was assessed in each group. Patients received a single oral dose of SDZ RAD (n=6) or placebo (n=3) with their usual Neoral dose. SDZ RAD and cyclosporin A pharmacokinetic parameters were determined. Results All SDZ RAD doses were well tolerated, with no discontinuations due to adverse events, serious adverse events, or deaths. Similar proportions of patients receiving SDZ RAD and placebo had at least one adverse event (44% and 50%, respectively). Mean changes in laboratory variables (baseline to endpoint) showed no clinically meaningful differences between SDZ RAD and placebo groups. SDZ RAD was absorbed rapidly and showed dose-proportional pharmacokinetics (dose: 2.5-25 mg), based on systemic exposure. Multiple postabsorptive phases in the pharmacokinetic profile indicate tissue distribution. The elimination half-life ranged from 24 to 35 h across the five highest dose groups. Pharmacokinetics were similar in men and women. Co-administration of escalating single oral SDZ RAD doses did not affect steady-state cyclosporin A pharmacokinetics. Conclusions SDZ RAD was well tolerated; safety profiles of SDZ RAD and placebo were similar. SDZ RAD pharmacokinetics were dose-proportional across the range 2.5-25 mg in conjunction with cyclosporin A-based therapy, according to systemic exposure. Cyclosporin A pharmacokinetics were not affected by coadministration of single oral doses of 0.25-25 mg SDZ RAD.Keywords: cyclosporin A, immunosuppressant, pharmacokinetics, safety, SDZ RAD, transplantation 40. This modification allowed the development of a solid Introduction dosage formulation that is more convenient to administer than rapamycin, which must be prepared from a The immunosuppressive properties of rapamycin have been known for more than 15 years [1, 2], but the refrigerated stock solution just before use. SDZ RAD has a mechanism of action similar to that of rapamycin: clinical development of the drug has been hampered by its limited oral bioavailability. A novel immunoinhibition of growth factor-driven proliferation of T cells and fibroblasts. SDZ RAD prevents graft rejection in rat suppressant, SDZ RAD, has recently been developed. SDZ RAD is a derivative of rapamycin but differs models of allotransplantation (kidney, heart) [3]. SDZ RAD and cyclosporin A show synergism in immunostructurally by having a 2-hydroxyethyl chain at position suppression both in vitro and in vivo [4].

mTOR inhibitors: An overview

“…However, in patients treated with sirolimus, no significant elevation of triglyceride serum levels was found, whereas treatment with RAD increased triglyceride levels by 459% using a dose of 2.5 mg/d and by 159% with a dose of 7.5 mg/d. In another study 83 evaluating single doses up to 25 mg of RAD in stable renal transplant recipients, the safety profiles of RAD and placebo were similar. Only mild or moderate side effects were seen after heart or heart and lung transplantation.…”

“…Because of its increased bioavailabil- ity, RAD shows a slightly greater AUC than sirolimus, but its half-life of 30 hours is much shorter than that of sirolimus. 22,26 Furthermore, the correlation between AUC and dose was stronger for RAD than for sirolimus, 83 and the pharmacokinetics of RAD are less affected by cyclosporine A than those of sirolimus. For these reasons, it was expected that RAD could be administered with cyclosporine A simultaneously.…”

Long-term outcome of everolimus treatment in transplant patients

“…14 Dose-proportional kinetics, as shown by the area under the blood-concentration time curve (AUC), were also reported after a single dose of everolimus (administered alone), 15 and after multiple doses of up to 5 mg/day. 16 Systemic exposure (AUC and C max ) was also dose-proportional in cardiac transplant recipients.…”

The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats

“…This agent was developed to prevent chronic graft rejection in solid organ transplantation. The short-term safety and tolerability of SDZ RAD in stable transplant recipients has been established [9,10], and studies assessing its efficacy in these patients and other solid organ recipients are ongoing. More recently, SDZ RAD has been shown to attenuate pulmonary arterial hypertension and neointimal formation induced by administration of monocrotaline in pneumonectomized rats [11].…”