Pharmacokinetic Steady-States Highlight Interesting Target-Mediated Disposition Properties

Gabrielsson, Johan; Peletier, L. A.

doi:10.1208/s12248-016-0031-y

Cited by 19 publications

(20 citation statements)

References 20 publications

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“…All of these observations are consistent with a saturable target-mediated clearance pathway, which markedly affects clearance at lower plasma concentrations but not at concentrations sufficiently high to saturate that pathway. 39 It should also be noted that, based on the AUC, the PK of dupilumab in monkeys, unlike that in humans, is approximately dose proportional (data on file, at Regeneron Pharmaceuticals, Inc., not shown). Because dupilumab does not bind monkey IL-R4α (data on file, Regeneron Pharmaceuticals, Inc.), dupilumab elimination in monkeys is not subject to target-mediated clearance, which is a reasonable explanation for species differences in PK; this provides additional evidence that the nonlinear PK profiles observed in the healthy subjects (but not in monkeys) are a result of binding to IL-4Rα.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in Healthy Adult Subjects

Radin

et al. 2020

Clinical Pharm in Drug Dev

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Dupilumab is a fully human monoclonal antibody directed against the interleukin (IL)-4 receptor α subunit (IL-4Rα) of IL-4 heterodimeric type I and type II receptors that mediate IL-4/IL-13 signaling through this pathway. Blockade of these receptors broadly suppresses type 2 inflammation associated with atopic/allergic diseases, including atopic dermatitis and asthma. Six phase 1 studies investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of dupilumab in healthy subjects. Two randomized, double-blind, placebo-controlled, sequential studies assessed safety and tolerability of single escalating dupilumab doses administered intravenously or subcutaneously (one included various racial groups, and one included exclusively Japanese subjects); 3 randomized, parallel-group, single-dose studies compared the pharmacokinetic profiles of different dupilumab products and formulations after single subcutaneous doses; and one study assessed dupilumab administered as fast versus slow subcutaneous injections. Dupilumab concentrations in serum were measured in all studies, and total immunoglobulin E (IgE) and thymus-and activation-regulated chemokine (TARC) concentrations were measured in 2 studies as pharmacodynamic markers. Across the phase 1 studies, dupilumab exhibited target-mediated pharmacokinetics consisting of parallel linear and nonlinear elimination, with the target-mediated phase highly dominated by nonlinearity at lower drug concentrations. Systemic exposure and tolerability of dupilumab were consistent irrespective of differences in product, formulation, or racial background. Dupilumab reduced circulating concentrations of total IgE and TARC, indicating blockade of IL-4Rα-mediated signaling. Dupilumab had a favorable safety profile across the wide range of doses administered. Together, these findings support the continued development and use of dupilumab in treatment of type 2 diseases.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in Healthy Adult Subjects

Radin

et al. 2020

Clinical Pharm in Drug Dev

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“…In this paper, we continue our study of in vivo potency of drug-target kinetics begun in Gabrielsson, Peletier et al and Hjorth et al (1,2) in the framework of Target-Mediated Drug Disposition (TMDD), an ubiquitous process in the action of drugs that has been extensively studied ever since the pioneering papers of Wagner (3), Sugiyama et al (4) and Levy (5). We also refer to the seminal papers by Michaelis and Menten (6), Mager and Jusko (7), Mager and Krzyzansky (8), Gibiansky et al (9) and Peletier and Gabrielsson (10).…”

Section: Introductionmentioning

confidence: 78%

New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition

Peletier

Gabrielsson

2018

AAPS J

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In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.

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“…Highly variable Ratios across compounds and targets are therefore not surprising. 31,32 A clear in vitro-to-in vivo correlation is not to be expected unless target-to-complex kinetics are constant or close to unity, and ligand-target removal is relatively slow (ligand-target complex elimination rate << ligand-target off-rate). 31,32 Failure to take target turnover and target-ligand complex characteristics into account is therefore likely to result in less predictable in vivo properties from in vitro potency readouts.…”

Section: In Vivo Potency Vs Target Turnovermentioning

confidence: 99%

Does In Vitro Potency Predict Clinically Efficacious Concentrations?

Jansson‐Löfmark

Stephan

Gabrielsson

2020

Clin Pharma and Therapeutics

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The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n = 164) and how they may differ depending on therapeutic indication, mode of action, receptor type, target localization, and function. Approximately 70% of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median ratio of exposure in relation to in vitro potency was 0.32, and 80% had ratios within the range of 0.007 to 8.7. We identified differences in the in vivo-to-in vitro potency ratio between indications, mode of action, target type, and matrix localization, and whether or not the drugs had active metabolites. The in vitro-assay variability contributions appeared to be the smallest; within the same drug target and mode of action the within-variability was slightly broader; but both were substantially less compared with the overall distribution of ratios. These data suggest that in vitro potency conditions, estimated in vivo potency, required level of receptor occupancy, and target turnover are key components for further understanding the link between clinical drug exposure and in vitro potency.

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Pharmacokinetic Steady-States Highlight Interesting Target-Mediated Disposition Properties

Cited by 19 publications

References 20 publications

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in Healthy Adult Subjects

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Dupilumab in Healthy Adult Subjects

New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition

Does In Vitro Potency Predict Clinically Efficacious Concentrations?

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