Development of a minimal physiologically-based pharmacokinetic/pharmacodynamic model to characterize target cell depletion and cytokine release for T cell-redirecting bispecific agents in humans

Jiang, Xiling; Chen, Xi; Jaiprasart, Pharavee; Carpenter, Thomas; Zhou, Rebecca; Wang, Weirong

doi:10.1016/j.ejps.2020.105260

Cited by 15 publications

(18 citation statements)

References 70 publications

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“…To address this challenge, a mPBPK model was developed and applied to account for the different characteristics of the two mAbs and predict the tissue site TE achieved by each drug at their respective dose regimens. Our groups have demonstrated the utility of mPBPK and mechanistic PK-TE-PD models for various biotherapeutics and targets with preclinical and translational applications ( Chen et al, 2016 ; Chen et al, 2018 ; Jiang et al, 2020 ; Zheng et al, 2020a ; Ayyar et al, 2021a ; Ayyar et al, 2021b ). In this study, a combined mPBPK-MBMA approach was taken to jointly examine clinical data from Phase 1-3 studies of secukinumab and ixekizumab.…”

Section: Discussionmentioning

confidence: 99%

Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis

et al. 2022

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The pharmacologic effect(s) of biotherapeutics directed against soluble targets are driven by the magnitude and duration of free target suppression at the tissue site(s) of action. Interleukin (IL)-17A is an inflammatory cytokine that plays a key role in the pathogenesis of psoriasis. In this work, clinical trial data from two monoclonal antibodies (mAbs) targeting IL-17A for treatment of psoriasis (secukinumab and ixekizumab) were analyzed simultaneously to quantitatively predict their target engagement (TE) profiles in psoriatic skin. First, a model-based meta-analysis (MBMA) for clinical responses was conducted separately for each drug based on dose. Next, a minimal physiologically-based pharmacokinetic (mPBPK) model was built to assess skin site IL-17A target engagement for ixekizumab and secukinumab simultaneously. The mPBPK model captured the observed drug PK, serum total IL-17A, and skin drug concentration-time profiles reasonably well across the different dosage regimens investigated. The developed mPBPK model was then used to predict the average TE (i.e., free IL-17A suppression) in skin achieved over a 12-weeks treatment period for each drug following their respective regimens and subsequently assess the TE-efficacy response relationship. It was predicted that secukinumab achieved 98.6% average TE in the skin at 300 mg q4w SC while ixekizumab achieved 99.9% average TE under 160 mg (loading) followed by 80 mg q2w SC. While direct quantification of free IL-17A levels at the site of action is technically challenging, integrated mPBPK-MBMA approaches offer quantitative predictions of free IL-17A levels at the site of action to facilitate future drug development via IL-17A suppression in psoriasis.

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Section: Discussionmentioning

confidence: 99%

Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis

et al. 2022

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“…In contrast to the complexity and variability of parameters in the full PBPK models, the minimal PBPK models have a simpler structure with a limited number of organs and can be used to describe the concentration profiles in specific tissues [ 112 , 121 , 122 , 123 , 129 , 131 , 132 , 133 , 134 , 135 , 136 ]. With minimal PBPK models, it is easy to incorporate additional tissue compartments, such as tumor and skin as the site of absorption, and additional kinetics, such as target antigen binding into the specific tissue compartments.…”

Section: Pbpk-model-based Prediction Of Human Pkpdmentioning

confidence: 99%

Recent Advances in Translational Pharmacokinetics and Pharmacodynamics Prediction of Therapeutic Antibodies Using Modeling and Simulation

Haraya¹,

Tsutsui²,

Komori³

et al. 2022

Pharmaceuticals

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Therapeutic monoclonal antibodies (mAbs) have been a promising therapeutic approach for several diseases and a wide variety of mAbs are being evaluated in clinical trials. To accelerate clinical development and improve the probability of success, pharmacokinetics and pharmacodynamics (PKPD) in humans must be predicted before clinical trials can begin. Traditionally, empirical-approach-based PKPD prediction has been applied for a long time. Recently, modeling and simulation (M&S) methods have also become valuable for quantitatively predicting PKPD in humans. Although several models (e.g., the compartment model, Michaelis–Menten model, target-mediated drug disposition model, and physiologically based pharmacokinetic model) have been established and used to predict the PKPD of mAbs in humans, more complex mechanistic models, such as the quantitative systemics pharmacology model, have been recently developed. This review summarizes the recent advances and future direction of M&S-based approaches to the quantitative prediction of human PKPD for mAbs.

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“…12,35,13 Recently, Jiang et al developed an integrated PBPK-PD model to describe the cytokine release profile and target cell depletion of blinatumomab in various patient populations following different dosing regimens. 37 Integrated PBPK-PD models illustrate the complex interaction between the TDB and its dual targets and can be envisaged to link its predicted target-site concentrations to outcomes and to understand response-heterogeneity. 37,38 Taken together, these integrated modeling approaches add multi-dimensional insights on the target engagement pharmacology and its relevance to clinical efficacy and safety.…”

Section: E-r For Safetymentioning

confidence: 99%

Quantitative Clinical Pharmacology of T‐Cell Engaging Bispecifics: Current Perspectives and Opportunities

Morcos¹,

Hosseini³

et al. 2020

Clinical Translational Sci

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T-cell directing/engaging bispecifics (TDBs) enable a powerful mode of action by activating T-cells through the creation of artificial immune synapses. Their pharmacological response involves the dynamic interrelationships between T-cells, tumor cells, and TDBs. This results in complex and challenging issues in understanding pharmacokinetics (PK), tissue distribution, target engagement, and exposure-response relationship. Dosing strategy plays a crucial role in determining the therapeutic window of TDBs because of the desire to maximize therapeutic efficacy in the context of known mechanism-related adverse events, such as cytokine release syndrome and neurological adverse events. Such adverse events are commonly reported as the most prominent events during the initial treatment cycles and dissipate over time. Therefore, the kinetic characterization of the interrelationships between exposure/target engagement and safety/efficacy outcomes is crucial in designing the optimal dosing regimen to maximize the benefit/risk of TDB agents. In this review, we discuss the key clinical pharmacological considerations in drug discovery and development for TDBs and provide a summary of TDBs currently in clinical development. We also propose forward-looking perspectives and opportunities to derive insights through quantitative clinical pharmacology approaches.

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Development of a minimal physiologically-based pharmacokinetic/pharmacodynamic model to characterize target cell depletion and cytokine release for T cell-redirecting bispecific agents in humans

Cited by 15 publications

References 70 publications

Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis

Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis

Recent Advances in Translational Pharmacokinetics and Pharmacodynamics Prediction of Therapeutic Antibodies Using Modeling and Simulation

Quantitative Clinical Pharmacology of T‐Cell Engaging Bispecifics: Current Perspectives and Opportunities

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