title: First time in human for GV196771: interspecies scaling applied on dose selection.
abstract: The utility of interspecies scaling in early drug development has been extensively debated. The authors discuss the dose selection strategy for a first time into man (FTIM) study for GV196771, a new glycine antagonist, using techniques of interspecies scaling. The FTIM dose selection strategy was based on predicted plasma profiles of GV196771 in humans using allometric scaling and considerations of safety and pharmacological activity in animals. Allometric techniques were first retrospectively applied to data obtained in humans and animals for GV150526, a glycine antagonist with similar pharmacokinetic characteristics to GV196771. GV196771 and GV150526 are extensively protein bound; thus, protein binding differences among species were considered in the scaling. Using the scaled pharmacokinetic parameters, compartmental modeling was performed to prospectively simulate concentration profiles for the oral administration of GV196771. This article will discuss the outcome of the prospective dose selection strategy for GV196771 compared to the actual concentration profiles observed in the FTIM study.
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Glaxo Wellcome SpA, Medicines Research Centre, Verona, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Iavarone
authors.forename: J F
authors.initials: JF
authors.lastname: Hoke
authors.forename: M
authors.initials: M
authors.lastname: Bottacini
authors.forename: R
authors.initials: R
authors.lastname: Barnaby
authors.forename: G C
authors.initials: GC
authors.lastname: Preston
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000254:growth & development; D004285:Dogs; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics*; D018684:Glycine Agents / Q000493:pharmacokinetics*; D006801:Humans; D007211:Indoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D009929:Organ Size / Q000187:drug effects; D011758:Pyrroles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity
chemical_list: C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D018691:Excitatory Amino Acid Antagonists; C119836:GV 196771A; D018684:Glycine Agents; D007211:Indoles; D011758:Pyrroles