Pharmacokinetics analysis based on target-mediated drug distribution for RC18, a novel BLyS/APRIL fusion protein to treat systemic lupus erythematosus and rheumatoid arthritis.

BACKGROUND AND PURPOSE:RC18 is a novel recombinant fusion protein targeting on B lymphocyte stimulator (BLyS). We aimed to develop and qualify a population pharmacokinetics (PopPK) model for RC18 in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, taking into account the mechanistic target-mediated drug disposition (TMDD) process. METHODS:A TMDD model of RC18 was developed using data from two phase I clinical trial (n = 23). The TMDD structural model was developed by simultaneous fitting of the serum free RC18 and serum RC18-BLyS complex. Potential covariates were screened using stepwise method, and predictive performance was qualified using a prediction-corrected visual predictive check (pcVPC) and bootstrap. RESULTS:A two compartment TMDD model with first order absorption for subcutaneous administration was built. The final model included a significant relationship between distribution volume of the central compartment and body weight. And the baseline of immunoglobulin IgG had significant effect on the baseline of target BLyS. The plots from goodness-of-fit and pcVPC confirmed good predictive performance of this TMDDmodel. CONCLUSIONS:This mechanistic TMDD model integrated the interaction of RC18 with its target BLyS and accurately predicts both RC18 and RC18-BLyS complex profiles in RA and SLE patients. Simulated target change profiles can be used to help guide rational dose regimen selection and used as a biomarker for efficacy evaluation.