title: Orthotopic liver transplantation using low-dose tacrolimus and sirolimus.
abstract: Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts (91%), with a follow-up of 23 months (range, 6 to 35 months). One episode (1.8%) of hepatic artery thrombosis was seen. The rate of acute cellular rejection was 14%. No extra treatment was administered in 3 of 8 patients, and the other 5 episodes responded to a single course of steroids. Cytomegalovirus infection occurred in 4 patients (7%). Renal function, glucose control, and lipid metabolism are near normal in 47 patients (84%) without additional medication. Steroid elimination is completed in 51 patients (91%). Bioavailability of SRL and TAC varied between transplant recipients, but trough levels strongly correlated with the area under the curve (r(2) = 0.82 and r(2) = 0.84, respectively). Simultaneous administration did not affect the PK profile of the drugs at this dose. The ratio of trough level to daily dose correlated between SRL and TAC. The synergistic effect seen in animal models also occurs in clinical liver transplant recipients on SRL-TAC combination immunosuppression. A low-dose combination of SRL and TAC should be compared with conventional immunosuppression in a multicenter, randomized, controlled trial.
authors.affiliation: Atlantic Canada Liver Transplantation Program, Dalhousie University, Halifax, Nova Scotia, Canada. vmcalist@uwo.ca
authors.forename: V C
authors.initials: VC
authors.lastname: McAlister
authors.forename: K M
authors.initials: KM
authors.lastname: Peltekian
authors.forename: D A
authors.initials: DA
authors.lastname: Malatjalian
authors.forename: S
authors.initials: S
authors.lastname: Colohan
authors.forename: S
authors.initials: S
authors.lastname: MacDonald
authors.forename: H
authors.initials: H
authors.lastname: Bitter-Suermann
authors.forename: A S
authors.initials: AS
authors.lastname: MacDonald
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003586:Cytomegalovirus Infections / Q000139:chemically induced / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D015994:Incidence; D008099:Liver / Q000201:enzymology; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D004338:Drug Combinations; D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus