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


CONCLUSIONS
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.
Kahan
B D
BD
Department of Surgery, University of Texas Medical School, Houston 77030, USA.
Wong
R L
RL
Carter
C
C
Katz
S H
SH
Von Fellenberg
J
J
Van Buren
C T
CT
Appel-Dingemanse
S
S
D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use*; D019233:Retreatment; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D011241:Prednisone; D020123:Sirolimus