Zotarolimus, a novel sirolimus analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression.
Sirolimus (rapamycin) is an immunosuppressant used in preventing allograft rejection and in drug-eluting stents to prevent restenosis after angioplasty. Zotarolimus, an analogue of sirolimus, was designed to have a shorter in vivo half-life. Zotarolimus was found to be mechanistically similar to sirolimus in having high-affinity binding to the immunophilin FKBP12 and comparable potency for inhibiting in vitro proliferation of both human and rat T cells. Rat pharmacokinetic studies with intravenous dosing demonstrated terminal elimination half-lives of 9.4 hours and 14.0 hours for zotarolimus and sirolimus, respectively. Given orally, T1/2 values were 7.9 hours and 33.4 hours, respectively. Consistent with its shorter duration, zotarolimus showed a corresponding and statistically significant 4-fold reduction in potency for systemic immunosuppression in 3 rat disease models. Pharmacokinetic studies in cynomolgus monkey underpredicted the half-life difference between zotarolimus and sirolimus apparent from recent clinical data. In vitro inhibition of human coronary artery smooth muscle cell proliferation by zotarolimus was comparable to sirolimus. Drug-eluting stents for local delivery of zotarolimus to the vessel wall of coronary arteries are in clinical development. The pharmacological profile of zotarolimus suggests it may be advantageous for preventing restenosis with a reduced potential for causing systemic immunosuppression or other side effects.
Chen
Yung-Wu
YW
Immunoscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois, USA.
Smith
Morey L
ML
Sheets
Michael
M
Ballaron
Steve
S
Trevillyan
James M
JM
Burke
Sandra E
SE
Rosenberg
Teresa
T
Henry
Cindy
C
Wagner
Rolf
R
Bauch
Joy
J
Marsh
Kennan
K
Fey
Thomas A
TA
Hsieh
Gin
G
Gauvin
Donna
D
Mollison
Karl W
KW
Carter
George W
GW
Djuric
Stevan W
SW
D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003331:Coronary Vessels / Q000166:cytology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000209:etiology / Q000517:prevention & control; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000517:prevention & control; D006084:Graft Rejection / Q000517:prevention & control*; D006207:Half-Life; D016027:Heart Transplantation; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects; D022061:Tacrolimus Binding Protein 1A / Q000187:drug effects
D007166:Immunosuppressive Agents; D022061:Tacrolimus Binding Protein 1A; C489443:zotarolimus; D020123:Sirolimus