Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper
Monoclonal antibodies (mAbs) deliver great benefits to patients with chronic and/or severe diseases thanks to their strong specificity to the therapeutic target. As a result of this specificity, non-human primates (NHP) are often the only preclinical species in which therapeutic antibodies cross-rea...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2022.2145997 |
| _version_ | 1798015621129043968 |
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| author | Karelle Ménochet Hongbin Yu Bonnie Wang Jay Tibbitts Cheng-Pang Hsu Amrita V. Kamath Wolfgang F. Richter Andreas Baumann |
| author_facet | Karelle Ménochet Hongbin Yu Bonnie Wang Jay Tibbitts Cheng-Pang Hsu Amrita V. Kamath Wolfgang F. Richter Andreas Baumann |
| author_sort | Karelle Ménochet |
| collection | DOAJ |
| description | Monoclonal antibodies (mAbs) deliver great benefits to patients with chronic and/or severe diseases thanks to their strong specificity to the therapeutic target. As a result of this specificity, non-human primates (NHP) are often the only preclinical species in which therapeutic antibodies cross-react with the target. Here, we highlight the value and limitations that NHP studies bring to the design of safe and efficient early clinical trials. Indeed, data generated in NHPs are integrated with in vitro information to predict the concentration/effect relationship in human, and therefore the doses to be tested in first-in-human trials. The similarities and differences in the systems defining the pharmacokinetics and pharmacodynamics (PKPD) of mAbs in NHP and human define the nature and the potential of the preclinical investigations performed in NHPs. Examples have been collated where the use of NHP was either pivotal to the design of the first-in-human trial or, inversely, led to the termination of a project prior to clinical development. The potential impact of immunogenicity on the results generated in NHPs is discussed. Strategies to optimize the use of NHPs for PKPD purposes include the addition of PD endpoints in safety assessment studies and the potential re-use of NHPs after non-terminal studies or cassette dosing several therapeutic agents of interest. Efforts are also made to reduce the use of NHPs in the industry through the use of in vitro systems, alternative in vivo models, and in silico approaches. In the case of prediction of ocular PK, the body of evidence gathered over the last two decades renders the use of NHPs obsolete. Expert perspectives, advantages, and pitfalls with these alternative approaches are shared in this review. |
| first_indexed | 2024-04-11T15:37:44Z |
| format | Article |
| id | doaj.art-0dd48640109d457fb44fab13cc929494 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-11T15:37:44Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-0dd48640109d457fb44fab13cc9294942022-12-22T04:15:55ZengTaylor & Francis GroupmAbs1942-08621942-08702022-12-0114110.1080/19420862.2022.2145997Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White PaperKarelle Ménochet0Hongbin Yu1Bonnie Wang2Jay Tibbitts3Cheng-Pang Hsu4Amrita V. Kamath5Wolfgang F. Richter6Andreas Baumann7Quantitative Discovery and Development, UCB, Slough, UKR&D Project Management and Development Strategies, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USANonclinical Disposition and Bioanalysis, Bristol Myers Squibb, Inc, Princeton, NJ, USANonclinical Development, South San Francisco, CA, USAPreclinical Development and Clinical Pharmacology, AskGene Pharma Inc, Camarillo, CA, USAPreclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc, South San Francisco, CA, USARoche Pharma Research and Early Development, Roche Innovation, Center Basel, F. Hoffmann-La Roche Ltd, Basel, SwitzerlandR&D, Bayer Pharma AG, Berlin, Germany & Non-clinical Biotech Consulting, Potsdam, Germany °(° present affiliation)Monoclonal antibodies (mAbs) deliver great benefits to patients with chronic and/or severe diseases thanks to their strong specificity to the therapeutic target. As a result of this specificity, non-human primates (NHP) are often the only preclinical species in which therapeutic antibodies cross-react with the target. Here, we highlight the value and limitations that NHP studies bring to the design of safe and efficient early clinical trials. Indeed, data generated in NHPs are integrated with in vitro information to predict the concentration/effect relationship in human, and therefore the doses to be tested in first-in-human trials. The similarities and differences in the systems defining the pharmacokinetics and pharmacodynamics (PKPD) of mAbs in NHP and human define the nature and the potential of the preclinical investigations performed in NHPs. Examples have been collated where the use of NHP was either pivotal to the design of the first-in-human trial or, inversely, led to the termination of a project prior to clinical development. The potential impact of immunogenicity on the results generated in NHPs is discussed. Strategies to optimize the use of NHPs for PKPD purposes include the addition of PD endpoints in safety assessment studies and the potential re-use of NHPs after non-terminal studies or cassette dosing several therapeutic agents of interest. Efforts are also made to reduce the use of NHPs in the industry through the use of in vitro systems, alternative in vivo models, and in silico approaches. In the case of prediction of ocular PK, the body of evidence gathered over the last two decades renders the use of NHPs obsolete. Expert perspectives, advantages, and pitfalls with these alternative approaches are shared in this review.https://www.tandfonline.com/doi/10.1080/19420862.2022.21459973Rsantibodiesdose predictionimmunogenicityNon-human primatenonspecific clearance |
| spellingShingle | Karelle Ménochet Hongbin Yu Bonnie Wang Jay Tibbitts Cheng-Pang Hsu Amrita V. Kamath Wolfgang F. Richter Andreas Baumann Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper mAbs 3Rs antibodies dose prediction immunogenicity Non-human primate nonspecific clearance |
| title | Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper |
| title_full | Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper |
| title_fullStr | Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper |
| title_full_unstemmed | Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper |
| title_short | Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper |
| title_sort | non human primates in the pkpd evaluation of biologics needs and options to reduce refine and replace a biosafe white paper |
| topic | 3Rs antibodies dose prediction immunogenicity Non-human primate nonspecific clearance |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2022.2145997 |
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