Absorption, Distribution, Metabolism, and Excretion (ADME) Studies of Biotherapeutics for Autoimmune and Inflammatory Conditions

Abstract

Abstract. Biotherapeutics are becoming an increasingly common drug class used to treat autoimmune and other inflammatory conditions. Optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of biotherapeutics is crucial for clinical, as well as commercial, success of these drugs. This review focuses on the common questions and challenges in ADME optimization of biotherapeutics for inflammatory conditions. For these immunomodulatory and/or immunosuppressive biotherapeutics, special consideration should be given to the assessment of the interdependency of ADME profiles, pharmacokinetic/pharmacodynamic (PK/PD) relationships, and immunogenicity profiles across various preclinical species and humans, including the interdependencies both in biology and in assay readouts. The context of usage, such as dosing regimens, extent of disease, concomitant medications, and drug product characteristics may have a direct or indirect (via modulation of immunogenicity) impact on ADME profiles of biotherapeutics. Along these lines, emerging topics include assessments of preexisting reactivity to a biotherapeutic agent, impact of immunogenicity on tissue exposure, and analysis of penetration to normal versus inflamed tissues. Because of the above complexities and interdependences, it is essential to interpret PK, PD, and anti-drug antibody results in an integrated manner. In addition, because of the competitive landscape in autoimmune and inflammatory markets, many pioneering ADME-centric protein engineering and subsequent in vivo testing (such as optimization of novel modalities to extend serum and tissue exposures and to improve bioavailability) are being conducted with biotherapeutics in this therapeutic area. However, the ultimate challenge is demonstration of the clinical relevance (or lack thereof) of modified ADME and immunogenicity profiles.

Network Pharmacology‐Based Study on the Mechanism of Pinellia ternata in Asthma Treatment

“…The components' data of PT originated from the TCMSP systems pharmacology database ( http://lsp.nwu.edu.cn/tcmsp.php ) [ 12 ]. To achieve the bioactive components' screening of PT in pharmacodynamics studies, two critical indicators have been usually taken as the screening criteria in ADME processes (e.g., absorption, distribution, metabolism, and excretion) and drug design, which include oral bioavailability (OB) and drug similarity (DL), and components were retained only if OB was over 30% and DL was more than 0.18 to satisfy criteria [ 13 ]. In this study, based on the relevant literature and the PubChem network database ( https://pubchem.ncbi.nlm.nih.gov/ ), 11 bioactive components of PT were retained, and their corresponding information (PubChem ID, OB, and DL) was also acquired for subsequent analysis [ 14 ].…”

Epilepsy therapy development: Technical and methodologic issues in studies with animal models

“…One third of the toxic side effects seen in humans cannot be predicted in any of the utilized nonhuman species (Baillie & Rettie, ). Poor predictability can arise because of species differences in absorption, distribution, metabolism, or excretion (ADME); PK; drug effects; or factors that affect the biologic activity of a drug, such as immunogenic reactions (Loscher et al., ; Baillie & Rettie, ; Vugmeyster et al., ). As a result, regulatory agencies generally require that toxicologic testing be conducted in two species (one rodent and one nonrodent).…”

A brief glimpse over the horizon for type 1 diabetes nanotherapeutics

“…Allergies including allergic asthma and severe food allergies affect~20% of the population while the prevalence of autoimmune diseases in the general population is currently at 4.5% [11][12][13][14][15][16][17]. The standard-of-care as well as emerging therapies are centered on systemic delivery of immunosuppresive drugs that require chronic administration which can exacerbate opportunistic infections, reactivate latent pathogens and can predispose to malignancy [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Emerging data indicate that other than targeting the specific effector cells involved in the actual tissue damage, it may be more attractive and easier, to target a therapeutic to the site(s) where immune cells acquire the ability to become effector cells (those that actually physically cause the damage, either by cytokines or by direct killing).…”