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Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection.

ABSTRACT: Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion-related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis and ankylosing spondylitis, respectively, to address the specified aims. Infliximab pharmacokinetics were well described by a 2-compartment model with linear mean estimated baseline clearance of 0.26 L/day. Alongside increased body weight, serum C-reactive protein, and antidrug antibody concentrations and decreased serum albumin, elevated serum glucose levels predicted higher clearance. In patients with rheumatoid arthritis, baseline infliximab clearance and body weight were the only identified predictors of early antidrug antibody detection. The odds ratio for antidrug antibody detection for each 0.1 L/day increase in baseline infliximab clearance was 1.78 (95% confidence interval, 1.50-2.12); for each 10-kg increase in body weight, this was 1.19 (1.06-1.33). Here we describe increased serum glucose levels as a novel independent predictor of baseline infliximab clearance. Estimates of baseline infliximab clearance should be incorporated to guide dosing modifications and/or antidrug antibody prophylaxis in clinical practice.

SUBMITTER: Eser A

PROVIDER: S-EPMC7821183 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection.

Eser Alexander A Reinisch Walter W Schreiber Stefan S Ahmad Tariq T Boulos Suliman S Mould Diane R DR

Journal of clinical pharmacology 20200909 2

Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion-related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANET ...[more]

PMID: 32905628

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Project description:: In oncology, an increasing number of targeted anticancer agents and immunotherapies are of biological origin. These biological drugs may trigger immune responses that lead to the formation of antidrug antibodies (ADAs). ADAs are directed against immunogenic parts of the drug and may affect efficacy and safety. In other medical fields, such as rheumatology and hematology, the relevance of ADA formation is well established. However, the relevance of ADAs in oncology is just starting to be recognized, and literature on this topic is scarce. In an attempt to fill this gap in the literature, we provide an up-to-date status of ADA formation in oncology. In this focused review, data on ADAs was extracted from 81 clinical trials with biological anticancer agents. We found that most biological anticancer drugs in these trials are immunogenic and induce ADAs (63%). However, it is difficult to establish the clinical relevance of these ADAs. In order to determine this relevance, the possible effects of ADAs on pharmacokinetics, efficacy, and safety parameters need to be investigated. Our data show that this was done in fewer than 50% of the trials. In addition, we describe the incidence and consequences of ADAs for registered agents. We highlight the challenges in ADA detection and argue for the importance of validating, standardizing, and describing well the used assays. Finally, we discuss prevention strategies such as immunosuppression and regimen adaptations. We encourage the launch of clinical trials that explore these strategies in oncology.Implications for practiceBecause of the increasing use of biologicals in oncology, many patients are at risk of developing antidrug antibodies (ADAs) during therapy. Although clinical consequences are uncertain, ADAs may affect pharmacokinetics, patient safety, and treatment efficacy. ADA detection and reporting is currently highly inconsistent, which makes it difficult to evaluate the clinical consequences. Standardized reporting of ADA investigations in the context of the aforementioned parameters is critical to understanding the relevance of ADA formation for each drug. Furthermore, the development of trials that specifically aim to investigate clinical prevention strategies in oncology is needed.

Project description:BackgroundInfliximab pharmacokinetic studies have been performed in patients receiving chronic infliximab therapy. In these patients, infliximab antidrug antibodies (ADAs) increase infliximab clearance and decrease serum levels and drug efficacy.ObjectiveThis study analyzed the pharmacokinetic effect of infliximab ADAs in healthy subjects receiving a single dose of intravenous infliximab.MethodsData were obtained from a single-blind, parallel-group, single-dose study of healthy subjects receiving 5 mg/kg of intravenous SB2 (infliximab biosimilar), EU-sourced Remicade (EU-IFX) or US-sourced Remicade (US-IFX). Serum infliximab was measured at 1, 2, 3, 6, 12, 24, 48, and 72 h and at 5, 7, 14, 21, 28, 42, 56, and 70 days after administration. ADAs were measured pre-dose and at 29 and 71 days. Data from the first ten subjects randomized to each treatment arm were utilized for this study. A two-compartment model of the serum infliximab vs. time curve was developed using nonlinear regression.ResultsAt 10 weeks, 11 subjects (37%) developed ADAs. ADAs were detected in four subjects after SB2, one subject after EU-IFX, and six subjects after US-IFX infusion. Of these, neutralizing antibodies occurred in one subject after SB2, in no subjects after EU-IFX, and in three subjects after US-IFX infusion. Infliximab clearance was increased in subjects with ADAs vs. those without ADAs (12.89 ± 2.69 vs. 9.90 ± 1.74 ml/h; p < 0.0005). The elimination half-time was shorter in subjects with ADAs (282.4 ± 56.4 vs. 343.3 ± 61.9 h; p < 0.01). Serum infliximab measured at 8 weeks correlated closely with infliximab clearance (R 2 = 0.5494; p < 0.0001).ConclusionADAs are common in healthy subjects after a single intravenous dose of infliximab and result in faster infliximab clearance, shorter elimination time, and lower serum infliximab levels. These data confirm that ADAs are common with biologic therapy and significantly impact the efficacy of these drugs.

Project description:Polymer conjugation is a clinically proven approach to generate long acting protein drugs with decreased immune responses. Although poly(ethylene glycol) (PEG) is one of the most commonly used conjugation partners due to its unstructured conformation, its therapeutic application is limited by its poor biodegradability, propensity to induce an anti-PEG immune response, and the resultant accelerated blood clearance (ABC) effect. Moreover, the prevailing preference of unstructured polymers for protein conjugation still lacks strong animal data support with appropriate control reagents. By using two biodegradable synthetic polypeptides with similar structural compositions (l-P(EG3Glu) and dl-P(EG3Glu)) for site-specific protein modification, in the current study, we systematically investigate the effect of the polymer conformation on the in vivo pharmacological performances of the resulting conjugates. Our results reveal that the conjugate l20K-IFN, interferon (IFN) modified with the helical polypeptide l-P(EG3Glu) shows improved binding affinity, in vitro antiproliferative activity, and in vivo efficacy compared to those modified with the unstructured polypeptide analogue dl-P(EG3Glu) or PEG. Moreover, l20K-IFN triggered significantly less antidrug and antipolymer antibodies than the other two. Importantly, the unusual findings observed in the IFN series are reproduced in a human growth hormone (GH) conjugate series. Subcutaneously infused l20K-GH, GH modified with l-P(EG3Glu), evokes considerably less anti-GH and antipolymer antibodies compared to those modified with dl-P(EG3Glu) or PEG (dl20K-GH or PEG20K-GH). As a result, repeated injections of dl20K-GH or PEG20K-GH, but not l20K-GH, result in a clear ABC effect and significantly diminished drug availability in the blood. Meanwhile, immature mouse bone marrow cells incubated with the helical l20K-GH exhibit decreased drug uptake and secretion of proinflammatory cytokines compared to those treated with one of the other two GH conjugates bearing unstructured polymers. Taken together, the current study highlights an urgent necessity to systematically reassess the pros and cons of choosing unstructured polymers for protein conjugation. Furthermore, our results also lay the foundation for the development of next-generation biohybrid drugs based on helical synthetic polypeptides.

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Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection.

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Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection.

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