title: Pharmacokinetic characterization of a natural product-inspired novel MEK1 inhibitor E6201 in preclinical species.
abstract: OBJECTIVE
  E6201 is a natural product-inspired novel inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEK1) and other kinases and is currently under development as an anticancer (parenteral administration) and antipsoriasis agent (topical application). In vitro and in vivo preclinical studies were performed to characterize the pharmacokinetics of E6201. Allometric scaling was applied to predict human pharmacokinetics of E6201.
  
  
  METHODS
  In vitro metabolism studies for CYP induction and CYP inhibition were conducted using human hepatocytes and microsomes, respectively. Metabolic stability using microsomes and protein-binding studies using pooled plasma were performed for mice, rats, dogs, and human. Pharmacokinetics of E6201 and its isomeric metabolite, ER-813010, in mice, rats, and dogs was determined following single IV administration of E6201 at three dose levels. Bioanalysis was performed using LC/MS/MS. Pharmacokinetic parameters were determined using non-compartmental analysis, and allometric scaling with a two-compartment model was used to predict E6201 pharmacokinetics in humans.
  
  
  RESULTS
  E6201 showed high plasma protein binding (>95%), and metabolic stability half-life ranged from 36 to 89 min across species. In vitro CYP inhibition (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A) and CYP induction (CYP1A, 3A, 2C9, and 2C19) suggested no inhibitory or induction effect on the tested human CYPs up to 10 μM of E6201. Pharmacokinetics of E6201 in mice, rats, and dogs was characterized by mean clearance ranging from 3.45 to 10.92 L/h/kg, distribution volume ranging from 0.63 to 13.09 L/kg, and elimination half-life ranging from 0.4 to 1.6 h. ER-813010 was detected in all species with metabolite to parent exposure ratio (AUC(R)) ranging from 3.1 to 33.4% and exhibited fast elimination (<3 h). The allometry predicted high clearance and large volume of distribution of E6201 in humans and was in general in good agreement with the observed first human subject pharmacokinetics.
  
  
  CONCLUSIONS
  E6201 exhibited high clearance, high to moderate distribution, and fast elimination in preclinical species. In vitro results suggested that E6201 has low risk of drug-drug interactions due to CYP inhibition and induction in humans. In the first-in-man study, E6201 exhibited high clearance, which was well predicted by allometric scaling.
authors.affiliation: Non-clinical Drug Development, Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, MA 02421, USA. vipul686@yahoo.com
authors.forename: Vipul
authors.initials: V
authors.lastname: Kumar
authors.forename: Edgar L
authors.initials: EL
authors.lastname: Schuck
authors.forename: Robert D
authors.initials: RD
authors.lastname: Pelletier
authors.forename: Nadia
authors.initials: N
authors.lastname: Farah
authors.forename: Krista B
authors.initials: KB
authors.lastname: Condon
authors.forename: Meng
authors.initials: M
authors.lastname: Ye
authors.forename: Christopher
authors.initials: C
authors.lastname: Rowbottom
authors.forename: Belinda M
authors.initials: BM
authors.lastname: King
authors.forename: Zhi-Yi
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Philip L
authors.initials: PL
authors.lastname: Saxton
authors.forename: Y Nancy
authors.initials: YN
authors.lastname: Wong
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: C545120:14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione; D065607:Cytochrome P-450 Enzyme Inhibitors; C570038:ER 813010; D007783:Lactones; D048369:MAP Kinase Kinase 1