Kinetics and Dynamics of Single Oral Doses of Sirolimus in Sixteen Renal Transplant Recipients

Abstract

Sirolimus is a new immunosuppressive drug that has been evaluated in animal experiments. The current study was conducted on humans with reformulated sirolimus in doses from 3 mg/m2 to 15 mg/m2. Sixteen renal transplant recipients were included in this phase I study to determine the safety, tolerance, and preliminary pharmacokinetics of increasing single doses of orally administered sirolimus. All 16 patients had stable renal graft function after a renal transplant at least 6 months before the study. Basal immunosuppression consisted of cyclosporine and prednisolone (n = 10) or cyclosporine, azathioprine, and prednisolone (n = 6). Four groups (I, 3 mg/m2; II, 5 mg/m2; III, 10 mg/m2; IV, 15 mg/m2) of four patients were assigned randomly to receive sirolimus (n = 3) or placebo (n = 1). Among the 12 patients who received sirolimus, five had mild transient study events such as headache, nausea, mild dizziness, hypoglycemia, epistaxis, and decrease in platelets. No serious adverse events occurred and no nephrotoxic effects could be related to the single dose administration of sirolimus. The only study event that was judged as probably related to sirolimus was the single case of thrombocytopenia. The other events were evaluated as possibly related. Thrombocytopenia occurred at the highest dose level (15 mg/m2 sirolimus). In two of the patients in the placebo group, slight elevations of liver enzymes and serum amylase were seen. Blood and plasma sirolimus concentrations were analyzed by an electrospray-high performance liquid/mass spectrophotometric (ESP-HPLC/MS) method Sirolimus showed an extensive red blood cell distribution with a mean blood/ plasma ratio of 49.1. The elimination half-life ranged from 43.8 to 86.5 hours (mean 56.9 hours). The Cmax and the area under the concentration versus time curves (AUC) correlated reasonably with doses from 3 to 15 mg/m2. The oral dose clearance ranged from 42 to 339 ml/h.kg. No clinically significant differences were seen in the trough concentrations of cyclosporine or the AUCs before and after the administration of sirolimus. Administration of single oral doses of sirolimus from 3 to 15 mg/m2 was safe and well tolerated in stable renal transplant recipients. Thrombocytopenia may be the dose-limiting toxicity. Additional phase II and phase III clinical trials will define the immunosuppressive efficacy of sirolimus.

Participation of Mammalian Target of Rapamycin Complex 1 in Toll-Like Receptor 2– and 4–Induced Neutrophil Activation and Acute Lung Injury

“…This dose of rapamycin was sufficent to inhibit mTORC1 activity 24 hours later in PAM-or LPS-exposed mice. In humans, a single dose of 5-20 mg/m 2 body surface area of rapamycin resulted in whole-blood concentrations 24 hours later of 8-30 ng/ml (i.e., 8.75-32.00 nM) (37), consistent with the 0-30 nM dose range that we used for in vitro experiments in neutrophils.…”

“…Vinciguerra and colleagues (35) found that rapamycin diminished phosphorylation of Ser 276 in the NF-kB p65 subunit and, in addition, also blocked nuclear localization of p65 in HepG2 cells stimulated with oleic acid. However, in the studies demonstrating inhibition of nuclear translocation of NF-kB by rapamycin, the concentrations used, from 200 nM to 10 mM, are much higher than those present in vivo after rapamycin administration (36,37). In our studies, exposure of neutrophils to rapamycin at lower concentrations that are similar to those found in vivo (30 nM) inhibited proinflammatory cytokine production, but did not affect TLR2- Figure 6.…”

Pharmacometrics and delivery of novel nanoformulated PEG-b-poly(ε-caprolactone) micelles of rapamycin

“…Therefore, a better understanding of the tissue distribution of rapamycin is warranted to try to establish a plausible relationship between its toxic effects and biodistribution. Furthermore, this extensive partitioning into tissues provides a relatively long half-life of more than 5 h up to 87 h [9,22,24] that permit once-a-day dosing, a delay in reaching steady-state concentrations [24,51], a wide inter-and intra-patient variability in drug clearance (0.090-0.339 l/h kg) [9,17,24] and a less than optimal correlation between blood or plasma concentrations and dose [30].…”

Systemic exposure of sirolimus after coronary stent implantation in patients with de novo coronary lesions: Supralimus-Core® pharmacokinetic study

“…Zimmerman and Kahan 14 reported the oral sirolimus t 1/2 to range from 60-83 hour following oral doses ranging from 0.5-6.5 mg/m 2 /12 hour (mean t 1/2 for all doses 62.3 hour). While Brattstrom et al 15 reported t 1/2 values ranging from 39 hours to 87 hours following oral doses ranging from 3 mg/m 2 to 15 mg/m 2 (mean t 1/2 for all doses 56.9 hours).…”