Steady-State Pharmacokinetics and Tolerability of Rad and Its Influence on Cyclosporine in Stable Renal Transplant Patients

This is the authors' abstract. We don't add key points for this paper.

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.