STEADY-STATE PHARMACOKINETICS AND TOLERABILITY OF RAD AND ITS INFLUENCE ON CYCLOSPORINE IN STABLE RENAL TRANSPLANT PATIENTS

Abstract

615 The disposition and tolerability of the immunosuppressant RAD, a hydroxyethyl derivative of rapamycin, were assessed in a placebo-controlled dose-escalation study in stable renal allograft recipients >6 months posttransplant. Study design: Groups of 6-12 patients receiving cyclosporine (Neoral) and steroids escalated through the following RAD regimens: 0.75, 2.5, 5, and 10 mg once daily (qd); 2.5 and 5 mg twice daily (bid). Pharmacokinetic profiles were assessed on days 1, 15, and 21. Cyclosporine profiles were assessed prestudy and again on day 21 with RAD or placebo. Tolerability: RAD was well tolerated up to 5 mg/day. Reversible, dose-dependent thrombocytopenia was observed. Hyperlipidemia was noted at the higher doses as described with rapamycin. Dose-proportionality: Both Cmax and AUC rose in a dose-proportional manner after the first dose and at steady state. Additionally, the exposure from the bid regimens (12-hr AUCs), when doubled, was not statistically different from those of the respective qd regimens (24-hr AUCs), p=0.67 Drug accumulation was ≤2-fold between first-dose and steady-state at day 15. (Table)Influence of a high-fat meal on RAD absorption: 6 patients receiving 2.5mg bid were randomized to take RAD under fasting or fed conditions at the day 15 and 21 visits. A high-fat meal slowed the rate of absorption (Cmax: 54 ± 15 vs 27 ± 14 ng/ml, p=0.01) but caused only a slight decrease in extent of absorption (AUC: 447 ± 193 vs 378 ± 235 ng·h/ml, p=0.12). Within-patient PK variability: Coefficients of variability from the replicate fasting profiles at steady-state (days 15 and 21) were ≤ 19% for both Cmax and AUC. Influence of RAD on CsA: The ratio of CsA AUCs (CsA with RAD or placebo divided by CsA alone) in placebo-treated patients was 1.19 ± 0.20 and did not differ among the RAD dosing cohorts (p=0.09). Conclusions: RAD was well tolerated at steady state up to 5 mg/day. Exposure was dose-proportional with low intra-patient variability up to 10 mg/day. RAD had no influence on CsA when both agents were coadministered at steady state.Table