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Cancer Chemother Pharmacol. 2016 Apr;77(4):767-76. doi: 10.1007/s00280-016-2992-z. Epub 2016 Feb 22.

Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies.

Author information

1
Department of Medical Oncology, Gustave Roussy, 114 Rue Edouard Vaillant, 94805, Villejuif, France. David.PLANCHARD@gustaveroussy.fr.
2
Quantitative Clinical Pharmacology, AstraZeneca, Macclesfield, UK.
3
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
4
Department of Oncology, Asan Medical Center, Seoul, Republic of Korea.
5
Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
6
Department of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
7
Quintiles Clinical Research Unit, Quintiles, Overland Park, KS, USA.
8
Research and Development, AstraZeneca, Macclesfield, UK.
9
Quantitative Clinical Pharmacology, AstraZeneca, Waltham, MA, USA.
10
Department of Adult Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
11
Formerly of Department of Medical Oncology, Christie Hospital, University of Manchester, Manchester, UK.
12
Seda Pharmaceutical Development Services, The Biohub at Alderley Park, Alderley Edge, Cheshire, SK10 4TG, UK.

Abstract

PURPOSE:

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.

KEYWORDS:

Bioavailability; Food effect; Multiple dose; Osimertinib; Pharmacokinetics; Single dose

PMID:
26902828
DOI:
10.1007/s00280-016-2992-z
[Indexed for MEDLINE]

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