Clinical pharmacokinetics of TNF antagonists: How do they differ?

doi:10.1016/j.semarthrit.2005.01.004

Seminars in Arthritis and Rheumatism

Volume 34, Issue 5, Supplement 1, April 2005, Pages 12-18

https://doi.org/10.1016/j.semarthrit.2005.01.004 Get rights and content

The relationship between the dose administered and the observed beneficial or adverse effects of a drug is one of the basic concepts of clinical pharmacology. The broad term “exposure” usually refers to the dose and the various acute or integrated measures of the resulting concentrations in blood (plasma, serum) and/or tissues/fluids. The term “response” refers to any direct measure of the pharmacologic effect (beneficial or otherwise) of the drug. Thus, as specified in a recent US Food and Drug Administration (FDA) Guidance for Industry (2004), “… a drug can be determined to be safe and effective only when the relationship of beneficial and adverse effect to a defined exposure is known.” Consequently, there has been a recent strong academic, industrial, and regulatory interest in exploring and characterizing the exposure-response relationships of existing and developed drugs. The first part of the cascade exposure, response cascade, is the relationship between the administered dose and the observed concentration-time profiles in the organism of interest, often referred to as pharmacokinetics (PK). The second part is the relationship between the concentration levels and the observed pharmacodynamic (PD) responses, often called PK-PD relationship. Within the causal chain of events after a drug is administered, the exposure (or PK) precedes the effect (or PD). Therefore, whenever any differentiation in the beneficial and/or adverse effects between drugs with similar mechanisms of action is observed, the underlying clinical PK is among the first considerations. The purpose of the current article is to review the PK properties of the 3 existing marketed tumor necrosis factor (TNF) antagonists, adalimumab (Abbott Laboratories), etanercept (Amgen Inc.), and infliximab (Centocor, Inc.), and to discuss the potential clinical implications of any PK differences.

Section snippets

Clinical pharmacokinetics of TNF antagonists

The “therapeutic window” paradigm provides the context in which the PK properties of 3 TNF antagonists are reviewed in this section. Only publicly available information has been used for the review.

Discussion

The existence of a causal relationship between exposure (PK) and response (efficacy and safety) means that if differences in the efficacy and safety characteristics among the 3 TNF antagonists are observed, the underlying differences in PK are the starting points for consideration. The differences in the observed concentration-time profiles of the drugs and the exposure characteristics derived from them are induced either by differences of the inherent properties of the molecules (ie, binding

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The global and economic success of immunoglobulin-based therapeutics in treating a wide range of diseases has heightened the need to further enhance their efficacy and lifetime while diminishing deleterious side effects. The three most ubiquitous challenges of therapeutic immunoglobulin delivery are their relatively short lifetimes in vivo, the immunologic consequences of soluble antibody-antigen complexes, and the emergence of anti-drug antibodies. We describe the rapid, cell-tolerated chemical engineering of the erythrocyte membrane in order to display any antibody, our model system being the display of anti-Tumor Necrosis Factor (anti-TNFα), on the surface of long-lived red blood cells (RBCs) while masking the antibody's Fc region. We developed four synthetic approaches to generate RBC-Staphylococcal protein A (RBC-SpA) complexes: amino group targeting through N-hydrosuccinidyl ester-functionalized homobifunctional poly(ethylene glycol) (NHS-PEG-NHS), direct thiol group targeting using heterobifunctional NHS-PEG-maleimide (NHS-PEG-MAL), converted thiol targeting using heterobifunctional NHS-PEG-MAL, and click chemistry using heterobifunctional NHS-PEG-azido (NHS-PEG-N₃) and NHS-PEG-alkyne (NHS-PEG-alk). The RBC-PEG-SpA complexes were formed within minutes, followed by the attachment of over 10⁵ antibodies per RBC to the accessible RBC-bound SpA via Fc-Protein A coupling. The RBC-PEG-SpA-antibody arrays were shown to be stable for more than 60 days in PBS and for more than 42 days in serum containing buffer. RBC-PEG-SpA-antibody complexes were shown to remove TNFα from physiological buffer and had similar mechanical properties to unmodified RBCs. Out of the four approaches, the converted thiol method provided the most controlled chemistry and construct stability. We are now ideally positioned to determine the long-term in vivo efficacy of chemically membrane-engineered RBCs to remove antigens, like TNFα, from serum.
The global and economic success of immunoglobulin-based therapeutics in treating a wide range of diseases has heightened the need to further enhance their efficacy and lifetime while diminishing deleterious side effects. The three most ubiquitous challenges of therapeutic immunoglobulin delivery are their relatively short lifetimes in vivo, the immunologic consequences of soluble antibody-antigen complexes, and the emergence of anti-drug antibodies. We describe the rapid, cell-tolerated chemical engineering of the erythrocyte membrane to display any antibody, our model system being the display of anti-Tumor Necrosis Factor (anti-TNFα), on the surface of long-lived red blood cells (RBCs) while masking the antibody's Fc region. Conversion of RBCs into therapeutic delivery vehicles, we argue, would enhance the circulation life of immunoglobulin-based therapeutics while simultaneously evading deleterious immune response.
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Population Pharmacokinetics and Exposure-Response Modeling Analyses of Golimumab in Children and Young Adults With Recently Diagnosed Type 1 Diabetes
2023, Journal of Clinical Pharmacology
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: This manuscript was prepared during the employment of the author with Amgen Inc., Thousand Oaks, CA 91320, USA.

View full text

Clinical pharmacokinetics of TNF antagonists: How do they differ?

Section snippets

Clinical pharmacokinetics of TNF antagonists

Discussion

Gastroenterology

J Am Acad Dermatol

Lancet

Disease severity in rheumatoid arthritisrelationships of plasma tumor necrosis factor-alpha, soluble interleukin 2-receptor, soluble CD4/CD8 ratio, neopterin, and fibrin D-dimer to traditional severity and functional measures

J Clin Immunol

Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis

Arthritis Rheum

Infiximab induces potent anti-inflammatory and local immunomodulatory activity but no systemic immune suppression in patients with Crohn’s disease

Aliment Pharmacol Ther

Pharmacokinetic considerations in treatment of inflammatory bowel disease

Clin Pharmacokinet

Cytokines in psoriasis

Int J Dermatol

Correlated increases of tumour necrosis factor-alpha, interleukin-6 and granulocyte monocyte-colony stimulating factor levels in suction blister fluids and sera of psoriatic patientsrelationships with disease severity

Clin Exp Dermatol

TNF-alpha and the TNF receptor superfamilystructure-function relationships

Microsc Res Tech

HUMIRA™ (adalimumab) Patient Information

Pharmacokinetic/pharmacodynamic (PK/PD) relationships of adalimumab (HUMIRA™) in rheumatoid arthritis (RA) patients during phase II/III clinical trials

Adalimumab efficacy and safety in patients with moderate to severe chronic plaque psoriasisPreliminary findings from a 12-week dose ranging trial

J Am Acad Dermatol

Steady-state pharmacokinetics (PK) of adalimumab (HUMIRA™) following 40 mg subcutaneous (sc) injection every other week (eow) in rheumatoid arthritis (RA) patients with and without methotrexate (MTX) background therapy

The effect of methotrexate (MTX) coadministration on the pharmacokinetics (PK) of adalimumab (HUMIRA™) following a single intravenous injection to rheumatoid arthritis patients