Estimating the contribution of everolimus to immunosuppressive efficacy when combined with tacrolimus in liver transplantation: A model-based approach

Determining the efficacy contribution of an investigational drug as part of a novel combination regimen that also includes a previously untested dose of a standard treatment is challenging, particularly when “placebo control” data (combination regimen minus the investigational drug) is not available...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2015-04, Vol.97 (4), p.411-418
Main Authors: Dumortier, T, Looby, M, Luttringer, O, Heimann, G, Klupp, J, Junge, G, Witte, S, VanValen, R, Stanski, D
Format: Article
Language:English
Subjects:
Adult
Aged
Drug Therapy, Combination
Everolimus
Female
Graft Rejection - prevention & control
Humans
Immunosuppressive Agents - pharmacokinetics
Immunosuppressive Agents - therapeutic use
Infant, Newborn
Liver Transplantation - methods
Male
Middle Aged
Sirolimus - analogs & derivatives
Sirolimus - pharmacokinetics
Sirolimus - therapeutic use
Tacrolimus - pharmacokinetics
Tacrolimus - therapeutic use
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Summary:Determining the efficacy contribution of an investigational drug as part of a novel combination regimen that also includes a previously untested dose of a standard treatment is challenging, particularly when “placebo control” data (combination regimen minus the investigational drug) is not available for comparison. This situation was encountered in a phase III trial that tested the combination of the investigational drug everolimus with a dose of tacrolimus lower than used in standard liver transplantation therapy. The challenge was addressed by predicting the efficacy of the placebo control from the study data using a pharmacometric‐based exposure–response analysis, selected to account for features specific to the transplant setting: systematic change in drug exposure over time and sparse pharmacokinetic sampling. The efficacy contribution of everolimus was then demonstrated by comparing this prediction to the efficacy of the combination regimen. This pharmacometrics‐based approach may contribute to characterization of therapeutic agents in real‐world settings.
ISSN:0009-9236
1532-6535
DOI:10.1002/cpt.63