Management of drug‐to‐drug interactions between cyclosporine A and the protease‐inhibitor lopinavir/ritonavir in liver‐transplanted HIV‐infected patients

• Published in: Liver transplantation Vol. 10; no. 7; pp. 939 - 944
• Main Authors: Vogel, Martin, Voigt, Esther, Michaelis, Hans‐Christoph, Sudhop, Thomas, Wolff, Martin, Türler, Andreas, Sauerbruch, Tilman, Rockstroh, Jürgen Kurt, Spengler, Ulrich
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2004
• Subjects: Adult; Cyclosporine - blood; Cyclosporine - pharmacokinetics; Cyclosporine - therapeutic use; Drug Interactions; Hepatitis C, Chronic - complications; Hepatitis C, Chronic - surgery; HIV Protease Inhibitors - therapeutic use; HIV Seropositivity - complications; HIV Seropositivity - drug therapy; Humans; Liver Transplantation - immunology; Lopinavir; Male; Middle Aged; Pyrimidinones - therapeutic use; Ritonavir - therapeutic use
• ISSN: 1527-6465; 1527-6473
• DOI: 10.1002/lt.20165

Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV‐infected patients, allowing orthotopic liver transplantation as a reasonable treatment option for selected patients with terminal liver disease. Both non‐nucleoside reverse transcriptase inhibitors and protease inhibitors, key elements of HAART, give rise to substantial drug‐to‐drug interactions with immunosuppressive drugs such as tacrolimus and cyclosporine A. After studying 12‐hour pharmacokinetic profiles in 3 HIV‐positive patients after liver transplantation, we describe how dosing of cyclosporine A can be adjusted to maintain effective immunosuppressive drug levels on a daily dosing schedule when ritonavir‐boosted indinavir or lopinavir‐based antiretroviral therapy is given. To avoid toxic drug levels, we used an orally available cyclosporine A formulation prepared from the commercial available intravenous solution, which enabled dose adjustments in 1‐mg increments. Under ritonavir‐boosted HAART, cyclosporine A levels showed markedly altered absorption/elimination characteristics with more or less constant blood‐levels throughout the dosing interval and prolonged elimination half‐lives up to 38 hours. To obtain equivalent areas under the curve of cyclosporine A, daily doses were reduced to 5–20% of the individual standard doses given before initiation of ritonavir‐boosted HAART. Because of the flat absorption/elimination profiles under ritonavir‐boosted HAART cyclosporine A, dosing could be reliably monitored long term by measuring cyclosporine A trough‐levels. (Liver Transpl 2004;10:939–944.)