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Physiologically-Based PK/PD Modelling of Therapeutic Macromolecules

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Abstract

Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules. The classical PBPK approach was discussed with a presentation of the successful example of PBPK modelling of cyclosporine A. PBPK model was performed with transport of the cyclosporine across cell membranes, affinity to plasma proteins and active membrane transporters included to describe drug transport between physiological compartments. For macromolecules, complex PBPK modelling or permeability-limited and/or target-mediated distribution was discussed. It was generally agreed that PBPK modelling was feasible and desirable. The role of the lymphatic system should be considered when absorption after extravascular administration is modelled. Target-mediated drug disposition was regarded as an important feature for generation of PK models. Complex PK-models may not be necessary when a limited number of organs are affected. More mechanistic PK/PD models will be relevant when adverse events/toxicity are included in the PK/PD modelling.

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Authors and Affiliations

  1. Exploratory ADME, Novo Nordisk A/S, Måløv, Denmark

    Peter Thygesen

  2. Laboratory of Biopharmaceutics and Pharmacokinetics, School of Pharmacy, University of Athens, Athens, Greece

    Panos Macheras

  3. Clinical Pharmacokinetics, Johnson and Johnson, Beerse, Belgium

    Achiel Van Peer

Authors
  1. Peter Thygesen
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  2. Panos Macheras
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  3. Achiel Van Peer
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Correspondence to Peter Thygesen.

Additional information

Meeting Report from an expert meeting organised by COST Action B25. The workshop entitled “Physiologically-based PK/PD modelling of therapeutic macromolecules” was held in Athens, 11 December 2006. COST is the acronym for European Cooperation in the Field of Scientific and Technical Research. COST Action B25 was launched in 2005 and is entitled “Physiologically based pharmaco-/toxicokinetics and dynamics.” Invited speakers gave presentations on various aspects of physiologically-based PK/PD modelling. Members of the COST Action B25, Working group 1 were Achiel Van Peer (Belgium), Panos Macheras (Greece), Peter Thygesen (Denmark), Constantin Mircioiu (Romania), Melih Babaoglu (Turkey), Jose A. Guimares Morais (Portugal), Jean-Louis Steimer (Switzerland). The invited experts were Stefan Willmann (Bayer Technology Services, Germany), Kim Kristensen (AstraZeneca, Sweden), Ryossei Kawai (Novartis, Japan), Phil Lowe (Novartis, Switzerland), Bill Jusko (University of Buffalo, USA) and Rune Overgaard (Novo Nordisk, Denmark). Lene Alifrangis (Novo Nordisk, Denmark) participated as an observer. The aims of the workshop were i) to discuss the feasibility of physiologically-based PK/PD modelling of therapeutic macromolecules, and ii) to identify important modelling issues with respect to therapeutic macromolecules.

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Thygesen, P., Macheras, P. & Van Peer, A. Physiologically-Based PK/PD Modelling of Therapeutic Macromolecules. Pharm Res 26, 2543–2550 (2009). https://doi.org/10.1007/s11095-009-9990-3

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  • DOI: https://doi.org/10.1007/s11095-009-9990-3

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