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 | Clinical Research Basic Scientific Principles |
| 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
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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.