title: mTOR inhibition in liver transplantation: how to dose for effective/safe CNI reduction?
abstract: Everolimus (EVR) is a semi-synthetic mammalian target of rapamycin inhibitor currently under development for liver transplantation (LTx) in combination with reduced exposure tacrolimus (rTAC). The relative potency of EVR was assessed in order to generate evidence for concomitant EVR+rTAC exposure in LTx recipients (LTxR). Twelve month data from study H2304 (NCT00622869), a 24-month, randomized, multicenter study in 719 de novo LTxR comparing EVR+rTAC to standard TAC demonstrated superior renal function and comparable efficacy, including fewer and less severe biopsy proven acute rejections with EVR+rTAC. Relative potency (p) of EVR was defined as factor by which the effect of 1 ng/mL of EVR must be multiplied to get comparable immunosuppression as with TAC: p = (TACcon - TACred)/EVRred. Relative efficacy of EVR in 4 different subpopulatlons was consistently 0.64, 0.60, 0.69, and 0.62, respectively. This assessment determined the relative potency of EVR as 0.64 compared to TAC in LTx indicating that EVR and TAC are not equipotent per ng/mL exposure. Knowledge about relative potency will help to rationalize co-exposure of EVR and TAC.
authors.affiliation: Department of Integrated Hospital Care (IHC), Basel, Switzerland. guido.junge@gmail.com
authors.forename: G
authors.initials: G
authors.lastname: Junge
authors.forename: T
authors.initials: T
authors.lastname: Dumortier
authors.forename: H
authors.initials: H
authors.lastname: Schwende
authors.forename: J
authors.initials: J
authors.lastname: Fung
mesh_terms: D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016031:Liver Transplantation; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus