Nonlinear Population Pharmacokinetics of Anifrolumab in Healthy Volunteers and Patients With Systemic Lupus Erythematosus

Abstract

We characterized the population pharmacokinetics of anifrolumab, a type I interferon receptor-blocking antibody. Pharmacokinetic data were analyzed from the anifrolumab (intravenous [IV], every 4 weeks) arms from 5 clinical trials in patients with systemic lupus erythematosus (SLE) (n = 664) and healthy volunteers (n = 6). Population pharmacokinetic modeling was performed using a 2-compartment model with parallel linear and nonlinear elimination pathways. The impact of covariates (demographics, interferon gene signature [IFNGS, high/low], disease characteristics, renal/hepatic function, SLE medications, and antidrug antibodies) on pharmacokinetics was evaluated. Time-varying clearance (CL) was characterized using an empirical sigmoidal time-dependent function. Anifrolumab exposure increased more than dose-proportionally from 100 to 1000 mg IV every 4 weeks. Based on population pharmacokinetics modeling, the baseline median linear CL was 0.193 L/day in IFNGS-high patients and 0.153 L/day in IFNGS-low/healthy volunteers. After a year, median anifrolumab linear CL decreased by 8.4% from baseline. Body weight and IFNGS were significant pharmacokinetic covariates, whereas age, sex, race, disease activity, SLE medications, and presence of antidrug antibodies had no significant effect on anifrolumab pharmacokinetics. Anifrolumab at a concentration of 300 mg IV every 4 weeks was predicted to be below the lower limit of quantitation in 95% of patients ≈10 weeks after a single dose and ≈16 weeks after stopping dosing at steady state. To conclude, anifrolumab exhibited nonlinear pharmacokinetics and time-varying linear CL; doses ≥300 mg IV every 4 weeks provided sustained anifrolumab concentrations. This study provides further evidence to support the use of anifrolumab 300 mg IV every 4 weeks in patients with moderate to severe SLE.

Keywords: drug development; modeling and simulation; pharmacodynamics; population pharmacokinetics; rheumatology.

Figure 1

Visual predictive check of the final updated population PK model showing anifrolumab concentration versus time for anifrolumab (a) 100 mg, (b) 150 mg, (c) 300 mg, and (d) 1000 mg. Dashed line (black) represents LLOQ (0.02 µg/mL). Shaded areas represent the 95%CI of the prediction. LLOQ, lower limit of quantification; PK, pharmacokinetic.

Figure 2

Model‐predicted concentration‐time profiles after a single dose of anifrolumab IV administration in (a) patients with a high type I IFNGS and (b) patients with a low IFNGS with SLE. ^a BW, body weight; IFNGS, interferon gene signature; IV, intravenous; LLOQ, lower limit of quantification (0.02 µg/mL); SLE, systemic lupus erythematosus. ^aAssumes typical patient BW of 70.0 kg.

Figure 3

Model‐predicted percentiles of anifrolumab washout concentration‐time profiles in the virtual patient population after (a) steady state (300 mg IV every 4 weeks) and (b) a single dose (300 mg IV). IC₅₀, potency, anifrolumab concentration corresponding to half‐maximum inhibition of PD signature production (0.971 µg/mL); IV, intravenous; LLOQ, lower limit of quantification (0.02 µg/mL); PD, pharmacodynamic.

Figure 4

Observed anifrolumab concentration over time by IFNGS status in patients with SLE in TULIP‐1 for anifrolumab (a) 150 mg and (b) 300 mg, and (c) in TULIP‐2 for anifrolumab 300 mg. Data were included from the phase 3 TULIP‐1 and TULIP‐2 trials (anifrolumab 150 mg [TULIP‐1 only], green; anifrolumab 300 mg, purple). IFNGS, interferon gene signature; SLE, systemic lupus erythematosus.

Figure 5

PD neutralization with anifrolumab 300 mg in patients with a high IFNGS with SLE by BW at baseline in the TULIP 1 and TULIP‐2 trials. BW, body weight; PD, pharmacodynamic; IFNGS, interferon gene signature; MAD, median absolute deviation; SLE, systemic lupus erythematosus.