AB0529 Population Pharmacokinetics of Atacicept in Systemic Lupus Erythematosus (SLE)

Papasouliotis, Orestis; Yalkinoglu, Özkan; Golob, Michaela; Willen, Daniela; Girard, Pascal

doi:10.1136/annrheumdis-2015-eular.3504

Cited by 4 publications

(7 citation statements)

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“…Atacicept showed evidence of efficacy in SLE in the phase II/III study APRIL-SLE and the phase IIb study ADDRESS II [ 18 , 35 ]. A summary of the PK parameters for atacicept as estimated from data are provided in the Supplementary Information; analysis of three clinical trials with the population PK model for atacicept can additionally be found in [ 37 , 38 ].…”

Section: Example: Ataciceptmentioning

confidence: 99%

Identifying Safety Thresholds for Immunosuppressive Drugs: Applying Insights from Primary Antibody Deficiencies to Mitigate Adverse Events in Secondary Antibody Deficiencies Using Mathematical Modeling of Preclinical and Early Clinical Data

Kareva

Zutshi

Mateo

et al. 2021

Eur J Drug Metab Pharmacokinet

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Immunosuppressive drugs can alleviate debilitating symptoms of autoimmune diseases, but, by the same token, excessive immune suppression can result in an increased risk of infection. Despite the dangers of a compromised immune system, clear definitions of what constitutes excessive suppression remain elusive. Here we review the most common infections associated with primary antibody deficiencies (PADs), such as agammaglobulinemia, common variable immunodeficiency (CVID), and IgA deficiency, as well as infections that are associated with drug-induced or secondary antibody immunodeficiencies (SADs). We identify a number of bacterial, viral, and fungal infections (e.g., Listeria monocytogenes , Staphylococcus sp., Salmonella spp., Escherichia coli , influenza, varicella zoster virus, and herpes simplex virus) associated with both PADs and SADs, and suggest that diagnostic criteria for PADs could be used as a first-line measure to identify potentially unsafe levels of immune suppression in SADs. Specifically, we suggest that, based on PAD diagnostic criteria, IgG levels should remain above 2–3 g/L, IgA levels should not fall below 0.07 g/L, and IgM levels should remain above 0.4 g/L to prevent immunosuppressive drugs from inducing mimicking PAD-like effects. We suggest that these criteria could be used in the early stages of drug development, and that pharmacokinetic and pharmacodynamic modeling could help guide patient selection to potentially improve drug safety. We illustrate the proposed approach using atacicept as an example and conclude with a discussion of the applicability of this approach for other drugs that may induce excessive immune suppression. Supplementary Information The online version contains supplementary material available at 10.1007/s13318-021-00706-z.

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Section: Example: Ataciceptmentioning

confidence: 99%

Identifying Safety Thresholds for Immunosuppressive Drugs: Applying Insights from Primary Antibody Deficiencies to Mitigate Adverse Events in Secondary Antibody Deficiencies Using Mathematical Modeling of Preclinical and Early Clinical Data

Kareva

Zutshi

Mateo

et al. 2021

Eur J Drug Metab Pharmacokinet

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“…The structural part of the base model of the present analysis was the same as the previous QSS TMDD model 14,22 . An IIV term for the first‐order K a was included, in addition to those for CL/ F , V c / F , V p / F , and R max , while using a diagonal Ω matrix.…”

Section: Resultsmentioning

confidence: 99%

“…A two‐compartment quasi‐steady‐state (QSS) approximation of the target‐mediated drug disposition (TMDD) binding model with first‐order absorption 20 , 21 had previously adequately described total atacicept concentrations from the phase I and phase II APRIL‐SLE studies. 14 , 22 This model is shown schematically in Figure S1 , together with the differential equations used.…”

Section: Methodsmentioning

confidence: 99%

Population pharmacokinetics of atacicept in systemic lupus erythematosus: An analysis of three clinical trials

Pitsiu¹,

Yalkinoglu

Farrell³

et al. 2023

CPT Pharmacom & Syst Pharma

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B cell stimulating factor (BLyS) and a proliferation‐inducing ligand (APRIL) are targets for novel treatments in patients with systemic lupus erythematosus (SLE). Atacicept is a recombinant, soluble fusion protein that blocks BLyS and APRIL activity. This study characterized the pharmacokinetic (PK) profile of atacicept using a population PK model and identified covariates explaining the PK variability. Total atacicept concentrations from a phase I study in healthy volunteers and two phase II studies in patients with SLE, using subcutaneous administration, were modeled using a quasi‐steady‐state approximation of the target‐mediated drug disposition model with first‐order absorption. The model included 3640 serum atacicept concentration records from 37 healthy volunteers and 503 patients with SLE and described total atacicept concentrations of the three trials, providing precise estimates of all parameters. Body weight and baseline BLyS concentration were the only statistically significant covariates, whereas no differences were found between patients and healthy volunteers. Apparent clearance and volume of the central compartment increased with body weight and initial target concentration increased with baseline BLyS. The change on atacicept exposure was moderate, with a difference in area under the curve compared with the median of 20%–32% for body weight, and 7%–18% for BLyS. Therefore, the effects of these covariates on atacicept exposure are not expected to be clinically relevant. The model described the complete total atacicept concentration–time profiles without finding any differences between healthy subjects and patients with SLE and supports the 150 mg once weekly dose for further trials.

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“…'Total' atacicept concentrations of PK samples were used to build a PK model for atacicept, as described (22) (and manuscript in preparation). Briefly, PK data were collected from double-blind, randomized, placebo-controlled clinical studies in which atacicept (25,75 and 150 mg) was given subcutaneously.…”

Section: Population Pk Modelmentioning

confidence: 99%

Kinetics of free and ligand-bound atacicept in human serum

et al. 2022

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BAFF (B cell activation factor of the TNF family/B lymphocyte stimulator, BLyS) and APRIL (a proliferation-inducing ligand) are targeted by atacicept, a decoy receptor consisting of the extracellular domain of TACI (transmembrane activator and calcium-modulator and cyclophilin (CAML) interactor) fused to the Fc portion of human IgG1. The purpose of the study was to characterize free and ligand-bound atacicept in humans. Total and active atacicept in serum of healthy volunteers receiving a single dose of subcutaneous atacicept or in patients treated weekly for one year were measured by ELISA, Western blot, or cell-based assays. Pharmacokinetics of free and bound atacicept were predicted based on total atacicept ELISA results. Persistence of complexes of purified atacicept bound to recombinant ligands was also monitored in mice. Results show that unbound or active atacicept in human serum exceeded 0.1 µg/ml for one week post administration, or throughout a 1-year treatment with weekly administrations. After a single administration of atacicept, endogenous BAFF bound to atacicept was detected after 8 h then increased about 100-fold within 2 to 4 weeks. Endogenous heteromers of BAFF and APRIL bound to atacicept also accumulated, but atacicept-APRIL complexes were not detected. In mice receiving intravenous injections of purified complexes pre-formed in vitro, atacicept-BAFF persisted longer (more than a week) than atacicept-APRIL (less than a day). Thus, only biologically inactive BAFF and BAFF-APRIL heteromers accumulate on atacicept in vivo. The measure of active atacicept provides further support for the once-weekly dosing regimen implemented in the clinical development of atacicept.

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AB0529 Population Pharmacokinetics of Atacicept in Systemic Lupus Erythematosus (SLE)

Cited by 4 publications

References 0 publications

Identifying Safety Thresholds for Immunosuppressive Drugs: Applying Insights from Primary Antibody Deficiencies to Mitigate Adverse Events in Secondary Antibody Deficiencies Using Mathematical Modeling of Preclinical and Early Clinical Data

Identifying Safety Thresholds for Immunosuppressive Drugs: Applying Insights from Primary Antibody Deficiencies to Mitigate Adverse Events in Secondary Antibody Deficiencies Using Mathematical Modeling of Preclinical and Early Clinical Data

Population pharmacokinetics of atacicept in systemic lupus erythematosus: An analysis of three clinical trials

Kinetics of free and ligand-bound atacicept in human serum

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