Efficacies of sirolimus (rapamycin) and cyclosporine in allograft vascular disease in non-human primates: trough levels of sirolimus correlate with inhibition of progression of arterial intimal thickening.
We investigated the efficacies of sirolimus (rapamycin) and cyclosporine for inhibition of graft vascular disease (GVD) in cynomolgus monkey recipients of aortic allografts. Increases in arterial intimal thickening in the midgraft (six consecutive cross-sections) after transplantation were quantified by serial intravascular ultrasound (IVUS) from day 21 to day 105. These data enabled correlations between changes in intimal indexes [II = (intimal area/vessel area) x 100] and trough levels of sirolimus and cyclosporine to be determined. Eighteen recipients received no immunosuppression for 6 weeks to allow alloimmune injury to occur. On day 45, monkeys were treated daily with sirolimus (n = 6) or cyclosporine (n = 6); six monkeys remained untreated. II increased significantly from day 63 to day 105 in untreated monkeys and monkeys treated with cyclosporine, whereas monkeys treated with sirolimus did not have a significant increase in II (P = 0.008, P = 0.006, P = NS; paired t-test). The change in II from days 63 to 105 was significantly greater in untreated monkeys compared to sirolimus-treated monkeys (P = 0.13; one-way ANOVA, P = 0.012 Tukey's post hoc test); other post hoc pairwise comparisons were not significant. Mean sirolimus and cyclosporine levels +/- SEM were 43 +/- 7 ng/ml and 562 +/- 20 ng/ml, respectively. Sirolimus trough levels, but not cyclosporine levels, correlated inversely with changes in II from day 42 to 105 (r2 = 0.73, P = 0.03). This non-human primate study shows that inhibition of intimal thickening by sirolimus depends on trough levels and provides the rationale for clinical trials of sirolimus for the control of GVD in organ transplant recipients.
Ikonen
T S
TS
Department of Cardiothoracic Surgery, Transplantation Immunology, Stanford University, CA 94305, USA.
Gummert
J F
JF
Serkova
N
N
Hayase
M
M
Honda
Y
Y
Kobayase
Y
Y
Hausen
B
B
Yock
P G
PG
Christians
U
U
Morris
R E
RE
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology* / Q000637:transplantation*; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018450:Disease Progression; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D012044:Regression Analysis; D020123:Sirolimus / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014184:Transplantation, Homologous / Q000276:immunology* / Q000473:pathology; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology / Q000637:transplantation*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus