Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics

Shah, Dhaval K.

doi:10.1007/s10928-015-9447-8

Cited by 44 publications

(40 citation statements)

References 82 publications

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“…rate and extent of distribution) that is required to predict the PK profiles with accuracy. Consequently, development of a platform PBPK model for protein therapeutics (13, 20) may be more appropriate if the goal is to a priori predict plasma and tissue PK of proteins.…”

Section: Discussionmentioning

confidence: 99%

Influence of Molecular size on the clearance of antibody fragments

Krippendorff

Shah

2017

Pharm Res

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Purpose To establish a continuous relationship between the size of various antibody fragments and their systemic clearance (CL) in mice. Methods Two different orthogonal approaches have been used to establish the relationship. First approach uses CL values estimated by non-compartmental analysis (NCA) to establish a correlation with protein size. The second approach simultaneously characterizes the PK data for all the proteins using a 2-compartment model to establish a relationship between protein size and pharmacokinetic (PK) parameters. Results Simple mathematical functions (e.g. sigmoidal, power law) were able to characterize the CL vs. protein size relationship generated using the investigated proteins. The relationship established in mouse was used to predict rat, rabbit, monkey, and human relationships using allometric scaling. The predicted relationships were found to capture the available spares data from each species reasonably well. Conclusions The CL vs. protein size relationship is important for establishing a robust quantitative structure-PK relationship (QSPKR) for protein therapeutics. The relationship presented here can help in a priori predicting plasma exposure of therapeutic proteins, and together with our previously established relationship between plasma and tissue concentrations of proteins, it can predict the tissue exposure of non-binding proteins simply based on molecular weight/radius and dose.

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Section: Discussionmentioning

confidence: 99%

Influence of Molecular size on the clearance of antibody fragments

Krippendorff

Shah

2017

Pharm Res

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“…ISF lying between the outer endothelial vessel wall and the plasma membranes of cells is the most relevant biological compartment for mAbs targeting cell surface antigens. 7 Thus determination of target site concentration is of paramount importance. Toward this, preclinical tissue distribution studies are performed using radiolabeled and/or nonlabeled mAbs to evaluate their concentrations in the tissues after homogenization.…”

Section: Discussionmentioning

confidence: 99%

Tissue Distribution of a Therapeutic Monoclonal Antibody Determined by Large Pore Microdialysis

Jadhav

Khaowroongrueng

Fueth

et al. 2017

Journal of Pharmaceutical Sciences

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“…Novel designed proteins meant as therapeutics to are subject to the same toxicity and pharmacokinetic constraints as other protein biologics [187]. In addition to affinity (or catalytic rate enhancement in the case of enzymes) and thermodynamic stability, a whole host of other properties must also be tuned to acceptable ranges including in vivo half-life, ADMET, off target effects, and others [188].…”

Section: Challenges In Automated Protein Designmentioning

confidence: 99%

Recent advances in automated protein design and its future challenges

Setiawan

Brender

Zhang

2018

Expert Opinion on Drug Discovery

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Introduction Protein function is determined by protein structure which is in turn determined by the corresponding protein sequence. If the rules that cause a protein to adopt a particular structure are understood, it should be possible to refine or even redefine the function of a protein by working backwards from the desired structure to the sequence. Automated protein design attempts to calculate the effects of mutations computationally with the goal of more radical or complex transformations than are accessible by experimental techniques. Areas covered The authors give a brief overview of the recent methodological advances in computer-aided protein design, showing how methodological choices affect final design and how automated protein design can be used to address problems considered beyond traditional protein engineering, including the creation of novel protein scaffolds for drug development. Also, the authors address specifically the future challenges in the development of automated protein design. Expert opinion Automated protein design holds potential as a protein engineering technique, particularly in cases where screening by combinatorial mutagenesis is problematic. Considering solubility and immunogenicity issues, automated protein design is initially more likely to make an impact as a research tool for exploring basic biology in drug discovery than in the design of protein biologics.

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Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics

Cited by 44 publications

References 82 publications

Influence of Molecular size on the clearance of antibody fragments

Influence of Molecular size on the clearance of antibody fragments

Tissue Distribution of a Therapeutic Monoclonal Antibody Determined by Large Pore Microdialysis

Recent advances in automated protein design and its future challenges

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