Abstract
Background
RAD is a novel macrolide with potent immunosuppressive and antiproliferative 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-period, two-sequence,
crossover study. Single doses of RAD capsules at doses of 0.035 mg/kg (2.5 mg maximum)
or 0.10 mg/kg (7.5 mg maximum) were administered with cyclosporine (Neoral [cyclosporine,
USP] modified), steroids, and azathioprine on Day 1. The alternate dose was administered
on Day 16. Laboratory assessments, vital signs, and adverse events were recorded throughout
the study. RAD pharmacokinetic profiles were assessed over a 7-day period following
each dose. Steady-state cyclosporine (CsA) profiles were assessed at baseline and
with each RAD dose; RAD and CsA trough concentrations were obtained throughout the
study period.
Results
Of the 20 patients randomized, 8 had CF and 12 did not. Single doses of RAD were safe
and well tolerated. Headache was the most common side effect. RAD produced a mild,
dose-dependent, reversible decrease in platelet and leukocyte counts. Cholesterol
and triglycerides were minimally affected. At both doses, CF patients had significantly
lower peak concentrations of 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 the higher dose, there was a clinically minor under-proportionality in
AUC, averaging −11%. Steady-state pharmacokinetics of CsA were not affected by RAD
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 influence the extent of RAD exposure.
Single doses of RAD did not affect the pharmacokinetics of CsA. Ongoing studies are
assessing the long-term safety and efficacy of RAD in lung and heart/lung transplantation.
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Article info
Publication history
Accepted:
October 20,
2000
Received:
July 20,
2000
Identification
Copyright
© 2001 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
