The US92 study determined whether, in de novo renal transplant patients, concentration-controlled everolimus (EVR) with reduced dose tacrolimus (RTAC) is non-inferior compared to CellCept®, (mycophenolate mofetil [MMF] with standard dose tacrolimus; STAC), with respect to allograft function and safety.

We investigated a center effect using the proportion of trough level values below 3 ng/mL (lower limit of EVR target range). A center was normally exposing (NE) if it had ≤30% of EVR trough levels <3 ng/mL. If >30% of EVR levels were <3 ng/mL, it was under-exposing (UE). Analyses accounting for the center effect were used to identify UE centers. Centers were ranked by two alternative (alt) methods, based on subjects' EVR concentrations predicted from a population pharmacokinetic model. The subjects' predicted EVR concentrations were ranked per day. In method one scoresforallsubjectswereaveragedbycenter. In method two the scores were averaged intoasubject'saveragescore, which wasaveragedbycenter. In a sensitivity approach, subgroups of UE and NE centers were defined for each method, and treatment groups were compared with incidence rates of the composite efficacy endpoint in NE centers.

EVR trough levels <3 or ≥3 ng/mL discriminated centers with a trend for normal or underexposure (table). Non-inferiority was shown for EVR to MMF for the composite endpoint in centers with ≤30% of EVR trough levels <3 ng/mL. Results were similar using the refined metrics

Lower EVR exposure is associated with higher treatment failure. It's important to maintain EVR drug levels between 3 to 8 ng/ml to achieve balance between efficacy and safety.

CITATION INFORMATION: Shihab F, Kaplan B, McCague K, Patel D, Vincenti F. Exposure Analysis for the Composite Efficacy Endpoints in the US92 Phase 3 Kidney Transplantation Trial to Understand Center Effects. Am J Transplant. 2016;16 (suppl 3).

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