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.
Background:In the TULIP-1 and TULIP-2 trials, anifrolumab, a type I interferon (IFN) receptor antibody, at a dosage of 300 mg once every 4 weeks (Q4W), demonstrated consistent median pharmacokinetic (PK) concentrations1 and sustained neutralization of the pharmacodynamic (PD) 21-gene type I IFN gene signature (IFNGS)2–4 in patients with moderate to severe systemic lupus erythematosus (SLE) despite standard therapy.Objectives:To characterize the PK/PD relationship of anifrolumab and to confirm anifrolumab 300 mg provides adequate PD neutralization in IFNGS test–high patients.Methods:This study included IFNGS test–high patients from the phase 3 randomized, placebo-controlled, 52-week TULIP-12 (NCT02446912) and TULIP-23 (NCT02446899) trials of intravenous anifrolumab 150 mg or 300 mg Q4W plus standard therapy. IFNGS test status (high or low) at screening was classified with an analytically validated 4-gene qPCR based test on whole blood.2 PD neutralization was measured with 21-gene type I IFNGS and expressed as a percentage change from baseline.3 For the graphic PK/PD analysis, patients with ≥1 quantifiable serum PK sample and ≥1 PD measurement before discontinuation were categorized depending on Cave (individual predicted average anifrolumab concentration over treatment duration) median and tertiles (T) for anifrolumab 150 mg and 300 mg, respectively. Median PD IFNGS neutralization and medium absolute deviations were compared across Cave subgroups. PK/PD modeling was assessed in patients with ≥1 quantifiable serum PK sample and a baseline and ≥1 postbaseline PD measurement before discontinuation, using a nonlinear mixed-effects model (NONMEM; version 7.3; ICON) to estimate parameters and characterize the PK/PD data. The PD/efficacy analysis included patients with ≥1 postbaseline PD measurement before discontinuation. BILAG-based Combined Lupus Assessment (BICLA) response rates at Week (W)52 were compared across median PD neutralization quartiles (Q) for pooled anifrolumab 300 mg and 150 mg groups.Results:The PK/PD graphic analysis included 654 IFNGS test–high patients (placebo [n=293]; anifrolumab 150 mg [n=72] or 300 mg [n=289]). Cave was generally higher with anifrolumab 300 mg (µg/mL, TULIP-1: T1 <32, T2 32–<44.3, T3 ≥44.3; TULIP-2: T1 <32.4, T2 32.4–<47.9, T3 ≥47.9) than with anifrolumab 150 mg (median 11.5 µg/mL); overlap between anifrolumab 300 mg and 150 mg Cave subgroups was small owing to nonlinearity. Anifrolumab 300 mg elicited rapid (by W44) and sustained median PD neutralization >80%, vs a lower and delayed PD neutralization (median >50% at W52) with anifrolumab 150 mg, and minimal PD neutralization with placebo. The median PD neutralization increased with higher Cave subgroups, plateauing at ~90% at W12–W52. All anifrolumab 300 mg Cave tertiles had a median PD neutralization ~80%; however, the variability was greater in the lowest Cave tertiles vs higher Cave tertiles across trials (Figure 1). The PK/PD modeling, which included 646 IFNGS test–high patients (placebo [n=289], anifrolumab 150 mg [n=70] or 300 mg [n=287]), gave an IC80 estimate of 3.88 μg/mL. The median W24 (study midpoint) Ctrough was higher with anifrolumab 300 mg vs 150 mg (15.6 vs 0.2 μg/mL); thus, the W24 Ctrough exceeded the IC80 in a higher proportion of patients treated with anifrolumab 300 mg vs 150 mg (~83% vs ~27%). The PD/efficacy analysis included 341 patients who received anifrolumab. Higher median percentage PD neutralization quartiles (Q1 <51.7%, Q2 51.7%–85.3%, Q3 85.3%–92.6%, Q4 >92.6%) were associated with higher W52 BICLA response rates (Q1 37.6%, Q2 49.4%, Q3 51.8%, Q4 58.1%).Conclusion:In TULIP-1 and TULIP-2, anifrolumab 300 mg yielded higher anifrolumab Cave vs 150 mg. High Cave was associated with rapid (W44–W12), substantial, and sustained PD neutralization of the 21-gene IFNGS in IFNGS test–high patients, which in turn was associated with higher efficacy.References:[1]Kuruvilla D. Poster 360, AAPS 2020.[2]Furie RA. Lancet Rheumatol. 2019;1:e208–19.[3]Morand EF. N Engl J Med. 2020;382:211–21.[4]Furie R. Arthritis Rheumatol. 2017;69:379–86.Acknowledgements:Writing assistance by Matilda Shackley, MPhil, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests:Yen Lin Chia Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca, Tu Mai Employee of: Genentech, Tomas Rouse Employee of: AstraZeneca, Wendy White Employee of: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca
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