Analysis of time course and dose effect of tacrolimus on proteinuria in lupus nephritis patients

Tacrolimus is used to treat patients with lupus nephritis; however, its time course and dose effect on proteinuria in lupus nephritis patients remain unknown. The purpose of this study was to determine the time course and dose effect of tacrolimus on proteinuria in lupus nephritis patients via model-based meta-analysis (MBMA).

PubMed, Web of Science, Cochrane Library and ClinicalTrials.gov databases were systematically searched for information on the efficacy of tacrolimus against proteinuria in lupus nephritis patients. Useful data were extracted to build a model for the population studied using a non-linear mixed-effect model (NONMEM). This model was applied to simulate time course of tacrolimus on proteinuria using Monte Carlo simulations.

Ten clinical studies that recruited 222 patients with lupus nephritis were included. Based on various diagnostic plots, we found that the established model described the observed data reasonably well. In addition, the typical E_max and ET₅₀ of tacrolimus for 24-hour proteinuria in lupus nephritis patients were -5.88 g and 0.37 months, respectively. The baseline value of 24-hour proteinuria affected E_max . No significant dose-response relationship was observed in the range of tacrolimus concentration used in the present study (3-10 ng/mL), indicating that the effect of tacrolimus on proteinuria depends on effective concentration range and not the dose. However, the time course relationship was obvious; the efficacy of tacrolimus increased over time, reaching a plateau (80% E_max ) at approximately 1.48 months from the beginning of treatment.

When the concentration range of tacrolimus is maintained at 3-10 ng/mL, at least 1.48 months of treatment is required to achieve a better outcome with regard to proteinuria in lupus nephritis patients.