¹Department of Pharmacy, Kyoto University Hospital, and Department of Transplantation and Immunology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

Correspondence: Ken-ichi Inui, PhD, Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan E-mail: inui@kuhp.kyoto-u.ac.jp

^*This work was supported in part by the 21st Century COE Program "Knowledge Information Infrastructure for Genome Science"; by a grant in aid from the Japan Health Sciences Foundation; by a grant in aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and by Novartis Ciclosporin Pharmaco-Clinical Forum Research Grant 2004. Masahide Fukudo is a Research Fellow of the Japan Society for the Promotion of Science.

Received 15 December 2004; Accepted 11 April 2005.

Abstract

Background: The calcineurin inhibitors tacrolimus and cyclosporine (INN, ciclosporin) have been widely used to prevent allograft rejection after transplantation. We investigated pharmacodynamic properties of the 2 drugs and their clinical relevance in liver transplantation.

Methods: Forty de novo living-donor liver transplant patients participated in this study, and they were treated with either tacrolimus (N = 30) or cyclosporine (N = 10). We simultaneously measured blood drug concentrations and calcineurin phosphatase activity in peripheral blood mononuclear cells during the first 14 postoperative days. Nephrotoxicity and acute rejection were also examined in relation to the blood drug concentrations and calcineurin activity.

Results: Calcineurin activity was only partially inhibited by tacrolimus concentrations greater than 20 ng/mL, although it could be almost completely inhibited by cyclosporine concentrations greater than 700 ng/mL. According to a maximum effect model, the population mean estimates of the EC₅₀ (blood concentration that yields a half-maximal effect) for tacrolimus and cyclosporine were 26.4 ng/mL (95% confidence interval [CI], 15.7-37.1 ng/mL) and 200 ng/mL (95% CI, 127-274 ng/mL), respectively. Patients with nephrotoxicity in both groups had significantly higher trough concentrations compared with those without this adverse event. In addition, patients with acute rejection in the tacrolimus group had significantly lower trough concentrations and higher calcineurin activity than those without a rejection episode.

Conclusions: The inhibitory effects on calcineurin activity in peripheral blood mononuclear cells differed between tacrolimus and cyclosporine in living-donor liver transplant patients. Pharmacodynamic assessment in combination with blood concentration monitoring may be useful for determining the individual therapeutic range of tacrolimus and cyclosporine.