464P - Preliminary AZD9291 Western and Asian clinical pharmacokinetics (PK) in patients (pts) and healthy volunteers (HV): Implications for formulation, d...

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Drug Development
Pharmacology
Presenter David Planchard
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors D. Planchard1, P.A. Dickinson2, K.H. Brown3, D. Kim4, S. Kim5, Y. Ohe6, E. Felip7, P. Leese8, M. Cantarini9, M. Ranson10
  • 1Medical Oncology, Gustave Roussy, 94805 - Villejuif/FR
  • 2Early Clinical Development, AstraZeneca, Macclesfield/GB
  • 3Global Clinical Development, AstraZeneca, Macclesfield/GB
  • 4Department Of Internal Medicine, Seoul National University Hospital, 110-744 - Seoul/KR
  • 5Medical Oncology, Asan Medical Center, 138736 - Seoul/KR
  • 6Department Of Thoracic Oncology, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
  • 7Thoracic Oncology Unit, Oncology Department, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 8N/a, Quintiles, Overland Park/US
  • 9Global Medicines Development, AstraZeneca, Macclesfield/GB
  • 10Department Of Medical Oncology, Formerly at University of Manchester Christie Hospital NHS Trust, Manchester/GB

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Abstract

Aim

AZD9291 is a selective, 3rd generation EGFR-TKI, effective against EGFR-TKI-sensitising and resistance T790M mutations preclinically. In a Phase I study of AZD9291 in pts with EGFRm+ NSCLC (NCT01802632) performed in the West and Asia, all dose levels (20–240 mg daily) resulted in tumour shrinkage. This study also provided capsule PK data at all doses and tablet PK at 80 mg. A relative bioavailability study in HV (NCT01951599) has provided single 20 mg dose data for capsule, solution and tablet formulations and will provide initial fed/fasted data.

Methods

In pts, plasma concentrations of AZD9291 (and potentially active metabolites AZ5104 and AZ7550) were determined up to 168 h following single dose and after 8 or 22 days of once daily dosing fasted. 197 pts received the capsule and 12 received the tablet. In HV, single dose PK were determined up to 504 h in a 3-period cross-over study. The impact of a high fat meal on PK will be investigated in a separate cohort. PK parameters were calculated using non-compartmental methods and nominal sample times.

Results

AZD9291 was slowly absorbed with a median (range) tmax of 6 (3–24) h across doses. Exposure was dose proportional across the 20–240 mg dose range. AZD9291 steady state appeared to be achieved by 22 days of dosing. The geomean accumulation of AZD9291 in plasma in pts was ∼4.5-fold, consistent with the dosing frequency and observed mean (range) half-life of 55 (30–145) h. AZD9291 PK appeared to be time independent. Initial assessment of key demographic factors (body weight, Asian/Caucasian ethnicity, sex and age) indicated no relationship between any demographic factor and PK. The tablet produced similar exposure to the capsule. Exposures of AZ5104 and AZ7550 were ∼10-fold lower than AZD9291. The PK in pts and HV were consistent.

Conclusions

PK results support once daily dosing, the same dose for all ethnic populations and switching from capsule to tablet in future studies. Plasma concentrations are sustained through the dosing period, which is considered optimal for efficacy and is supported by the tumour responses observed. Updated information will be provided.

Disclosure

D. Planchard: Advisory boards: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Roche, BMS; P.A. Dickinson, K.H. Brown and M. Cantarini: Employment and stock ownership: AstraZeneca; E. Felip: Advisory boards: Boehringer Ingelheim, Novartis, Roche, BMS, Lilly; P. Leese: Employment: Quintiles (the CRO contracted to do the study); M. Ranson: Advisory board: AstraZeneca. All other authors have declared no conflicts of interest.