BACKGROUND AND OBJECTIVES: Sifalimumab is a fully human immunoglobulin G1κ 
monoclonal antibody that binds to and neutralizes a majority of the subtypes of 
human interferon-α. Sifalimumab is being evaluated as a treatment for systemic 
lupus erythematosus (SLE). The primary objectives of this analysis were (a) to 
develop a population pharmacokinetic model for sifalimumab in SLE; (b) to 
identify and quantitate the impact of patient/disease characteristics on 
pharmacokinetic variability; and (c) to evaluate fixed versus body weight 
(WT)-based dosing regimens.
METHODS: Sifalimumab serum concentration-time data were collected from a phase 
Ib study (MI-CP152) designed to evaluate the safety and tolerability of 
sifalimumab in adult patients with SLE. Sifalimumab was administered every 14 
days as a 30- to 60-minute intravenous infusion with escalating doses of 0.3, 
1.0, 3.0, and 10 mg/kg and serum concentrations were collected over 350 days. A 
total of 120 patients provided evaluable pharmacokinetic data with a total of 
2,370 serum concentrations. Sifalimumab serum concentrations were determined 
using a validated colorimetric enzyme-linked immunosorbent assay (ELISA) with a 
lower limit of quantitation of 1.25 μg/mL. Population pharmacokinetic modeling 
of sifalimumab was performed using a non-linear mixed effects modeling approach 
with NONMEM VII software. Impact of patient demographics, clinical indices, and 
biomarkers on pharmacokinetic parameters were explored using a stepwise forward 
selection and backward elimination approach. The appropriateness of the final 
model was tested using visual predictive check (VPC). The impact of body 
WT-based and fixed dosing of sifalimumab was evaluated using a simulation 
approach. The final population model was utilized for phase IIb dosing 
projections.
RESULTS: Sifalimumab pharmacokinetics were best described using a 
two-compartment linear model with first order elimination. Following intravenous 
dosing, the typical clearance (CL) and central volume of distribution (V 1) were 
estimated to be 176 mL/day and 2.9 L, respectively. The estimates (coefficient 
of variation) of between-subject variability for CL and V 1 were 28 and 31 %, 
respectively. Patient baseline body WT, interferon gene signature from 21 genes, 
steroid use, and sifalimumab dose were identified as significant covariates for 
CL, whereas only baseline body WT was a significant covariate for V 1 and 
peripheral volume of distribution (V 2). Although the above-mentioned covariates 
were statistically significant, they did not explain variability in 
pharmacokinetic parameters to any relevant extent (<7 %). Thus, no dosing 
adjustments are necessary. VPC confirmed good predictability of the final 
population pharmacokinetic model. Simulation results demonstrate that both fixed 
and body WT-based dosing regimens yield similar median steady state 
concentrations and overall variability. Fixed sifalimumab doses of 200, 600, and 
1,200 mg monthly (with a loading dose at Day 14) were selected for a phase IIb 
clinical trial.
CONCLUSION: A two-compartment population pharmacokinetic model adequately 
described sifalimumab pharmacokinetics. The estimated typical pharmacokinetic 
parameters were similar to other monoclonal antibodies without target mediated 
elimination. Although the population pharmacokinetic analysis identified some 
statistically significant covariates, they explained <7 % between-subject 
variability in pharmacokinetic parameters indicating that these covariates are 
not clinically relevant. The population pharmacokinetic analysis also 
demonstrated the feasibility of switching to fixed doses in phase IIb clinical 
trials of sifalimumab.