Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients.
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.
Vogel
Martin
M
Department of Internal Medicine I, University of Bonn, Germany.
Voigt
Esther
E
Michaelis
Hans-Christoph
HC
Sudhop
Thomas
T
Wolff
Martin
M
Türler
Andreas
A
Sauerbruch
Tilman
T
Rockstroh
Jürgen Kurt
JK
Spengler
Ulrich
U
D000328:Adult; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006679:HIV Seropositivity / Q000150:complications / Q000188:drug therapy*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000601:surgery*; D006801:Humans; D016031:Liver Transplantation / Q000276:immunology*; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D011744:Pyrimidinones / Q000627:therapeutic use*; D019438:Ritonavir / Q000627:therapeutic use*
D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D016572:Cyclosporine; D019438:Ritonavir