title: Pharmacokinetic drivers of toxicity for basic molecules: strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor.
abstract: Several toxicities are clearly driven by free drug concentrations in plasma, such as toxicities related to on-target exaggerated pharmacology or off-target pharmacological activity associated with receptors, enzymes or ion channels. However, there are examples in which organ toxicities appear to correlate better with total drug concentrations in the target tissues, rather than with free drug concentrations in plasma. Here we present a case study in which a small molecule Met inhibitor, GEN-203, with significant liver and bone marrow toxicity in preclinical species was modified with the intention of increasing the safety margin. GEN-203 is a lipophilic weak base as demonstrated by its physicochemical and structural properties: high LogD (distribution coefficient) (4.3) and high measured pKa (7.45) due to the basic amine (N-ethyl-3-fluoro-4-aminopiperidine). The physicochemical properties of GEN-203 were hypothesized to drive the high distribution of this compound to tissues as evidenced by a moderately-high volume of distribution (Vd>3l/kg) in mouse and subsequent toxicities of the compound. Specifically, the basicity of GEN-203 was decreased through addition of a second fluorine in the 3-position of the aminopiperidine to yield GEN-890 (N-ethyl-3,3-difluoro-4-aminopiperidine), which decreased the volume of distribution of the compound in mouse (Vd=1.0l/kg), decreased its tissue drug concentrations and led to decreased toxicity in mice. This strategy suggests that when toxicity is driven by tissue drug concentrations, optimization of the physicochemical parameters that drive tissue distribution can result in decreased drug concentrations in tissues, resulting in lower toxicity and improved safety margins.
authors.affiliation: Safety Assessment, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. diaz.dolores@gene.com
authors.forename: Dolores
authors.initials: D
authors.lastname: Diaz
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Ford
authors.forename: Dylan P
authors.initials: DP
authors.lastname: Hartley
authors.forename: Eric B
authors.initials: EB
authors.lastname: Harstad
authors.forename: Gary R
authors.initials: GR
authors.lastname: Cain
authors.forename: Kirsten
authors.initials: K
authors.lastname: Achilles-Poon
authors.forename: Trung
authors.initials: T
authors.lastname: Nguyen
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
authors.forename: John J
authors.initials: JJ
authors.lastname: Gaudino
authors.forename: Robert
authors.initials: R
authors.lastname: Kaus
authors.forename: Sock C
authors.initials: SC
authors.lastname: Lewin-Koh
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.forename: Donna M
authors.initials: DM
authors.lastname: Dambach
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011897:Random Allocation; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D047428:Protein Kinase Inhibitors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met