A phase I study of a 4-week course of SDZ-RAD (RAD) quiescent cyclosporine-prednisone-treated renal transplant recipients

Transplantation. 1999 Oct 27;68(8):1100-6. doi: 10.1097/00007890-199910270-00007.

Abstract

Background and methods: This phase I, randomized, blinded, placebo-controlled study assessed the safety profile and pharmacokinetics of a 4-week course of once-daily, sequential ascending doses (0.75, 2.5, or 7.5 mg/day) of SDZ-RAD (RAD) capsules in renal transplant recipients on a stable regimen of cyclosporine (CsA; Neoral) and prednisone.

Results: RAD displayed a similar spectrum of side effects as observed with rapamycin, namely, an increased incidence of infection associated with the augmented immunosuppression and a dose-related occurrence of thrombocytopenia, hypercholesterolemia, and hypertriglyceridemia, particularly at the 7.5-mg dose. The pharmacokinetic parameters of RAD showed dose proportionality, a good correlation between trough and area under the curve (AUC) concentrations, and a moderate accumulation of 2.5-fold. The drug was absorbed within 2 hr and displayed a 16-19-hr half-life, which is shorter than that of rapamycin. RAD reached steady state at 4 days. Preliminary kinetic-dynamic correlations indicate a correlation between thrombocytopenia (but not hyperlipidemia) and AUC, as well as maximum drug concentrations, and weight-adjusted dose. At the end of a 4-week course of simultaneous dosing, there was no evidence of a pharmacokinetic interaction between CsA and RAD.

Conclusion: This study suggests that the shorter half-life of RAD compared to rapamycin may confer the benefits of rapid attainment of steady state and dissipation of effects upon drug cessation. Controlled, multicenter trials are being planned to assess the impact of these features on clinical outcomes.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Cyclosporine / therapeutic use*
  • Double-Blind Method
  • Drug Administration Schedule
  • Everolimus
  • Female
  • Glucocorticoids / therapeutic use*
  • Half-Life
  • Humans
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / pharmacokinetics
  • Immunosuppressive Agents / therapeutic use
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Prednisone / therapeutic use*
  • Retreatment
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacokinetics
  • Sirolimus / therapeutic use

Substances

  • Glucocorticoids
  • Immunosuppressive Agents
  • Cyclosporine
  • Everolimus
  • Prednisone
  • Sirolimus