IMMUNOSUPPRESSION RAD in Stable Lung and Heart/Lung Transplant Recipients: Safety, Tolerability, Pharmacokinetics, and Impact of Cystic Fibrosis Ramona L. Doyle, MD, a Marshall I. Hertz, MD, b Jordan M. Dunitz, MD, b J. E. Loyd, MD, c Arlene A. Stecenko, MD, c Robert L. Wong, MD, d Kimberly A. Chappell, PharmD, d Tim Brazelton, MD, a John M. Kovarik, PhD, FCP, e Silke Appeldingemanse, MD, e Lin Dou, PhD, d Harold T. Smith, PhD, d David Tudor, PhD, d and Randall E. Morris, MD a 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. From the a Stanford University School of Medicine, Stanford, California; b University of Minnesota, Minneapolis, Minnesota; c Vanderbilt University, Nashville, Tennessee; d Novartis Phar- maceuticals Corporation, East Hanover, New Jersey; and e Novartis Pharma AG, Basel, Switzerland. Submitted July 20, 2000; accepted October 20, 2000. Reprint requests: Ramona L. Doyle, MD, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305. Telephone: 650-723-6381. Fax: 650-725-5489. Copyright © 2001 by the International Society for Heart and Lung Transplantation. 1053-2498/01/$–see front matter PII S1053-2498(00)00232-1 330