title: The virtue of translational PKPD modeling in drug discovery: selecting the right clinical candidate while sparing animal lives.
abstract: Translational pharmacokinetic-pharmacodynamic (PKPD) modeling has been fully implemented at AstraZeneca's drug discovery unit for central nervous system and pain indications to facilitate timely progression of the right compound to clinical studies, simultaneously assuring essential preclinical efficacy and safety knowledge. This review illustrates the impact of a translational PKPD paradigm with examples from drug discovery programs. Paradoxically, laboratory animal use decreased owing to better understanding of in vitro-in vivo relationships, optimized in vivo study designs, meta-analyses and hypothesis testing using simulations. From an ethical and effectivity perspective, we advocate that translational PKPD approaches should be implemented more broadly in drug discovery.
authors.affiliation: AstraZeneca R&D Innovative Medicines Unit, Central Nervous System and Pain, SE-15185 Södertälje, Sweden. tjerk.bueters@merck.com
authors.forename: Tjerk
authors.initials: T
authors.lastname: Bueters
authors.forename: Bart A
authors.initials: BA
authors.lastname: Ploeger
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D061214:Patient Safety; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D010599:Pharmacokinetics; D018570:Risk Assessment; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014116:Toxicology; D057170:Translational Research, Biomedical
chemical_list: D004364:Pharmaceutical Preparations