Pharmacodynamic analysis of tacrolimus and cyclosporine in living-donor liver transplant patients.
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 EC(50) (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.
Fukudo
Masahide
M
Department of Pharmacy, Kyoto University Hospital, Japan.
Yano
Ikuko
I
Masuda
Satohiro
S
Fukatsu
Sachio
S
Katsura
Toshiya
T
Ogura
Yasuhiro
Y
Oike
Fumitaka
F
Takada
Yasutsugu
Y
Tanaka
Koichi
K
Inui
Ken-ichi
K
D000284:Administration, Oral; D019703:Calcineurin / Q000187:drug effects* / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus