title: Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies.
abstract: OBJECTIVE
  Osimertinib (AZD9291) 80 mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure.
  
  
  METHODS
  AURA (NCT01802632): single- and multiple-dose PK of osimertinib (20-240 mg daily) was determined in patients with advanced NSCLC. Bioavailability study (NCT01951599): single-dose PK of osimertinib (20 mg) was determined in healthy volunteers with administration of capsule, solution, or tablet formulations fasted, and as a tablet in the fed and fasted state.
  
  
  RESULTS
  Osimertinib was slowly absorbed and displayed dose-proportional increases in exposure from 20 to 240 mg. Distribution was extensive and clearance low to moderate, resulting in a mean half-life of 48.3 h. Steady state was achieved by 15 days of dosing, consistent with single-dose PK, with a peak-to-trough ratio of 1.6. Two active metabolites circulated at ~10 % of osimertinib exposure. Ethnicity did not appear to affect exposure. Osimertinib PK profiles in healthy volunteers were similar to those in patients and were unaffected by formulation. Food caused a clinically insignificant increase in exposure.
  
  
  CONCLUSIONS
  Osimertinib PK supports once-daily dosing; the same dose for Asian and non-Asian populations; a fixed-dosing approach; a minimal effect of food on exposure; and a switch to tablet formulation without alteration to dose or schedule. Osimertinib plasma concentrations are sustained throughout the dosing period, which is considered optimal for efficacy.
authors.affiliation: Department of Medical Oncology, Gustave Roussy, 114 Rue Edouard Vaillant, 94805, Villejuif, France. David.PLANCHARD@gustaveroussy.fr.
authors.forename: David
authors.initials: D
authors.lastname: Planchard
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Macclesfield, UK.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Brown
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Sang-We
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.affiliation: Department of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.affiliation: Quintiles Clinical Research Unit, Quintiles, Overland Park, KS, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Leese
authors.affiliation: Research and Development, AstraZeneca, Macclesfield, UK.
authors.forename: Mireille
authors.initials: M
authors.lastname: Cantarini
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, MA, USA.
authors.forename: Karthick
authors.initials: K
authors.lastname: Vishwanathan
authors.affiliation: Department of Adult Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Formerly of Department of Medical Oncology, Christie Hospital, University of Manchester, Manchester, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Macclesfield, UK.|Seda Pharmaceutical Development Services, The Biohub at Alderley Park, Alderley Edge, Cheshire, SK10 4TG, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dickinson
mesh_terms: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D044466:Asian People; D002626:Chemistry, Pharmaceutical; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines
keywords: Bioavailability; Food effect; Multiple dose; Osimertinib; Pharmacokinetics; Single dose