Population pharmacokinetics of sifalimumab, an investigational anti-interferon-monoclonal antibody, in systemic lupus erythematosus patients

Background/Purpose: Sifalimumab is a fully human immunoglobulin (Ig) G1k monoclonal antibody (mAb) that binds to and neutralizes a majority of the subtypes of human IFN-a. Sifalimumab is being evaluated as a treatment for systemic lupus erythematosus (SLE). The primary objectives of this analysis were to (a) model the population pharmacokinetics (PK) of sifalimumab; (b) to identify and quantitate the impact of patient/disease characteristics on PK variability; and (c) to evaluate fixed versus body weight based dosing regimens. Methods: Sifalimumab serum concentration-time data were collected from a phase 1b study (Study # MI-CP152) designed to evaluate the safety and tolerability of multiple IV doses of sifalimumab in adult patients with SLE. Sifalimumab was administered every 14 days as a 60-minute IV infusion with escalating doses of 0.3, 1.0, 3.0 and 10 mg/kg and trough serum concentrations were collected every 14 days. A total of 120 patients provided evaluable PK data with a total of 2370 serum concentrations (average of 20 samples per patient). Sifalimumab serum concentrations were determined using a validated colorimetric enzyme-linked immunosorbent assay (ELISA) with a lower limit of quantitation (LLOQ) of 1.25 mg/mL. The population PK of sifalimumab was performed using a non-linear mixed effects modeling approach in NONMEM VII software. Impact of patient demographics, clinical indices and biomarkers on PK parameters were explored using a step wise forward selection and backward elimination approach. The appropriateness of the final model was tested using visual predictive check (VPC). The final population PK model was utilized for phase II dosing projections. Results: Sifalimumab PK was best described using a 2-compartment linear model with first order elimination. Following IV dosing, the typical clearance (CL) and central volume of distribution (Vc) were estimated tobe 176 mL/day and 2.9 L, respectively. The estimates of between-subject variability for CL and Vc were 28% and 31%, respectively. Patient baseline body weight, IFN gene signature (21 genes), steroid use and sifalimumab dose were identified as significant covariates for CL, whereas only baseline body weight was significant covariate for Vc and Vp. Although the above mentioned covariates were statistically significant, they did not explain variability in sifalimumab PK parameters to any relevant extent. Thus no dosing adjustments are necessary. VPC results demonstrated good predictability of the final population PK model. Simulation results demonstrate that both fixed and body weight based dosing regimens yield similar median steady state concentrations (Css) and variability. Fixed sifalimumab doses of 200, 600 and 1200 mg monthly (with a loading dose at day 14) were selected for phase II clinical trial. Conclusion: A population PK model of sifalimumab was developed and validated. The estimated typical PK parameters were similar to other monoclonal antibodies without a target sink. The population PK analysis also demonstrated the feasibility of evaluating fixed doses of sifalimumab in phase II clinical trials.