title: Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors.
abstract: OBJECTIVE
  Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients.
  
  
  METHODS
  A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design.
  
  
  RESULTS
  The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37).
  
  
  CONCLUSIONS
  These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Monica M
authors.initials: MM
authors.lastname: Mita
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.forename: Jung Ah
authors.initials: JA
authors.lastname: Jung
authors.forename: Claudio Dansky
authors.initials: CD
authors.lastname: Ullmann
authors.forename: Catherine
authors.initials: C
authors.lastname: Milch
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D005260:Female; D065569:Gastrointestinal Absorption; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019999:Pharmaceutical Solutions; D011208:Powders; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D002214:Capsules; C550258:MLN 8237; D019999:Pharmaceutical Solutions; D011208:Powders; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A