RAD in stable lung and heart/lung transplant recipients: safety, tolerability, pharmacokinetics, and impact of cystic fibrosis
| Autor: | Jordan M. Dunitz, Ramona L. Doyle, David Tudor, James E. Loyd, John M. Kovarik, Marshall I. Hertz, R. Wong, Lin Dou, Silke Appel-Dingemanse, Kimberly A Chappell, Arlene A. Stecenko, Harold T. Smith, Timothy R. Brazelton, Randall E. Morris |
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| Rok vydání: | 2001 |
| Předmět: |
Adult
Male Pulmonary and Respiratory Medicine medicine.medical_specialty Adolescent Cystic Fibrosis Side effect Heart-Lung Transplantation medicine.medical_treatment Gastroenterology Double-Blind Method Pharmacokinetics Internal medicine medicine Humans Lung transplantation Transplantation Cross-Over Studies business.industry Area under the curve Middle Aged Ciclosporin Crossover study Endocrinology Tolerability Cyclosporine Female Surgery Macrolides Cardiology and Cardiovascular Medicine business Immunosuppressive Agents Lung Transplantation medicine.drug |
| Zdroj: | The Journal of Heart and Lung Transplantation. 20:330-339 |
| ISSN: | 1053-2498 |
| DOI: | 10.1016/s1053-2498(00)00232-1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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