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

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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.

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Acknowledgments

The authors would like to thank Hal Galbraith, Quintiles, and Rupert Austin, BAST Inc., for pharmacokinetic analysis of NCA parameters in the bioavailability and AURA studies, respectively, and the staff and investigators at all 34 study sites for AURA: Australia: Thomas John, Michael Millward, Chee Lee; France: David Planchard, Jaafar Bennouna, Benoit You; Germany: Jürgen Wolf, Martin Schuler, Barbara Deschler-Baier; Japan: Yuichiro Ohe, Naoyuki Nogami, Yasuhito Fujisaka, Takashi Seto, Takayasu Kurata, Toshiaki Takahashi; Republic of Korea: Sang-We Kim, Dong-Wan Kim, Myung-Ju Ahn, Joo-Hang Kim; Spain: Enriqueta Felip, Luis Paz Ares, José Antonio López Martín; Taiwan: James Chih-Hsin Yang, Josh Chia-Chi Lin, Wen-Pin Su; UK: Malcolm R. Ranson, Fiona Blackhall, Ruth Plummer; USA: Pasi Jänne, Kathryn Gold, Ross Camidge, Leora Horn, Suresh Ramalingam, Daniel Haggstrom. We thank Donna Tillotson PhD, from iMed Comms, an Ashfield Company, who provided editing assistance funded by AstraZeneca.

Funding

These studies (NCT01802632 and NCT01951599) were sponsored by AstraZeneca.

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Correspondence to David Planchard.

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Conflict of interest

David Planchard has received remuneration for consultancy/advisory boards from AstraZeneca. Enriqueta Filip has received remuneration for consultancy/speaker’s bureaus from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Pfizer, and Roche. Kathryn Brown, Mireille Cantarini, and Karthick Vishwanathan are employees and shareholders of AstraZeneca. Pasi Jänne has received consulting fees from AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Genentech, Merrimack Pharmaceuticals, Chugai, and Pfizer. He has received post-marketing royalties from a Dana-Farber Cancer Institute-owned patent on EGFR mutations licensed to Lab Corp, and has stock ownership in Gatekeeper Pharmaceuticals. Malcom Ranson has received remuneration for consultancy/advisory board from AstraZeneca. Paul Dickinson is a shareholder of AstraZeneca and also Managing Director of Seda Pharma Development Services, which has a contract to provide services to AstraZeneca. Dong-Wan Kim declares that he has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Planchard, D., Brown, K.H., Kim, DW. et al. Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies. Cancer Chemother Pharmacol 77, 767–776 (2016). https://doi.org/10.1007/s00280-016-2992-z

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  • DOI: https://doi.org/10.1007/s00280-016-2992-z

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