RAD in stable lung and heart/lung transplant recipients: Safety, tolerability, pharmacokinetics, and impact of cystic fibrosis

Background: RAD is a novel macrolide with potent immunosuppressive and anti proliferative activities. This study characterizes the safety, tolerability , and pharmacokinetics of two different single oral doses of RAD in stable lung and heart/lung transplant recipients with and without cystic fibrosis (CF). Methods: This was a Phase I, multicenter, randomized, double-blind, two-per iod, two-sequence, crossover study. Single doses of RAD capsules at doses o f 0.035 mg/kg (2.5 mg maximum) or 0.10 mg/kg (7.5 mg maximum) were administ ered with cyclosporine (Neoral [cyclosporine, USP] modified), steroids, and azathioprine on Day 1. The alternate dose was administered on Day 16. Labo ratory assessments, vital signs, and adverse events were recorded throughou t the study. RAD pharmacokinetic profiles were assessed over a 7-day period following each dose. Steady-state cyclosporine (CsA) profiles were assesse d at baseline and with each RAD dose; RAD and CsA trough concentrations wer e obtained throughout the study period. Results: Of the 20 patients randomized, 8 had CF and 12 did not. Single dos es of RAD were safe and well tolerated. Headache was the most common side e ffect. RAD produced a mild, dose-dependent, reversible decrease in platelet and leukocyte counts. Cholesterol and triglycerides were minimally affecte d. At both doses, CF patients had significantly lower peak concentrations o f RAD than did non-CF patients (p = 0.03); however, overall exposure (area under the curve/dose) was not different between the groups (p = 0.63). At t he higher dose, there was a clinically minor under-proportionality in AUC, averaging -11%. Steady-state pharmacokinetics of CsA were not affected by R AD co-administration. Conclusions: RAD was safe and well tolerated by stable lung and heart/lung transplant recipients with and without CF. The presence of CF did not influ ence the extent of RAD exposure. Single doses of RAD did not affect the pha rmacokinetics of CsA. Ongoing studies are assessing the long-term safety an d efficacy of RAD in lung and heart/lung transplantation.