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Single- and multiple-dose pharmacokinetics, potential for CYP3A inhibition, and food effect in patients with cancer and healthy subjects receiving ipatasertib

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Abstract

Purpose

To examine the single- and multiple-dose pharmacokinetics (PK), CYP3A inhibition potential of ipatasertib, and effect of food on PK of ipatasertib in patients with refractory solid tumors and a dedicated food effect assessment in healthy subjects.

Methods

The Phase I dose-escalation study enrolled patients with solid tumors in a standard 3 + 3 design with a 1 week washout after the first dose, followed by once-daily dosing on a 3-week-on/1-week-off schedule. In the expansion cohort, the effect of ipatasertib on CYP3A substrate (midazolam) was assessed by examining the change in midazolam exposure when dosed in the absence and presence of steady-state ipatasertib at 600 mg. The effect of food on ipatasertib PK was studied with ipatasertib administered in fed or fasted state (6 patients from Phase I patient study and 18 healthy subjects from the dedicated food effect study).

Results

Ipatasertib was generally well tolerated at doses up to 600 mg given daily for 21 days. Ipatasertib showed rapid absorption (tmax, 0.5–3 h), was dose-proportional over a range of 200–800 mg, had a median half-life (range) of 45.0 h (27.8–66.9 h), and had approximately two-fold accumulation following once-daily dosing. Midazolam exposure (AUC0-∞) increased by 2.2-fold in the presence of ipatasertib. PK was comparable in subjects administered ipatasertib in a fed or fasted state.

Conclusion

Ipatasertib exhibited rapid absorption and was dose-proportional over a broad dose range. Ipatasertib appeared to be a moderate CYP3A inhibitor when administered at 600 mg and could be administered with or without food in clinical studies.

Trail registration

NCT01090960 (registered March 23, 2010); NCT02536391 (registered August 31, 2015).

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Availability of data and material

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

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Acknowledgements

The study was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland, and Genentech, Inc., a member of the Roche Group, South San Francisco, CA, USA. The authors would also like to thank all participating patients and their families. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd.

Funding

The study was funded by F. Hoffmann-La Roche Ltd., Basel, Switzerland, and Genentech, Inc., a member of the Roche Group, South San Francisco, CA, USA.

Author information

Authors and Affiliations

  1. Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA

    Vikram Malhi, Rucha Sane & Luna Musib

  2. Clinical Pharmacology, BeiGene, San Mateo, CA, USA

    Nageshwar Budha

  3. Safety Science, Genentech, Inc., South San Francisco, CA, USA

    Jian Huang & Yuzhong Deng

  4. Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA

    Bianca Liederer

  5. Clinical Science, Genentech, Inc., South San Francisco, CA, USA

    Raymond Meng

  6. eFFECTOR Therapeutics, Inc., San Diego, CA, USA

    Premal Patel

  7. INCLIVA, University of Valencia, Valencia, Spain

    Andres Cervantes

  8. Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain

    Josep Tabernero

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  1. Vikram Malhi
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Contributions

VM contributed to data analysis and interpretation, writing the initial draft, revision of the manuscript for critically important content, and approval of final manuscript submission. NB, RS, JH contributed to data analysis and interpretation, revision of the manuscript for critically important content, and approval of final manuscript submission. BL contributed to study design, revision of the manuscript for critically important content, and approval of final manuscript submission. RM, PP contributed to study design, data analysis and interpretation, revision of the manuscript for critically important content, and approval of final manuscript submission. YD contributed to study design, data collection, revision of the manuscript for critically important content, and approval of final manuscript submission. AC, JT contributed to the study design, data collection revision of the manuscript for critically important content and approval of final manuscript submission. LM contributed to study design, data analysis and interpretation, writing the initial draft, revision of the manuscript for critically important content, and approval of final manuscript submission.

Corresponding author

Correspondence to Vikram Malhi.

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Conflict of interest

Authors Vikram Malhi, Nageshwar Budha, Rucha Sane, Jian Huang, Bianca Liederer, Raymond Meng, Premal Patel, Yuzhong Deng, Luna Musib are or were Genentech employees and owned Roche stock at the time of this study. Author Josep Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech, Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. Author Andres Cervantes reports institutional research funding from Astellas, Bayer, BeiGene, Bristol-Myers Squibb, Fibrogen, Genentech, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Roche, Servier, Takeda; advisory board or speaker fees: Astellas, Merck Serono, Roche, Servier, Takeda.

Ethical approval

Studies were conducted in accordance with good clinical practice guidelines, applicable laws, and regulations, and in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Regulatory authorities and institutional review boards approved the study. Additional approval for the Phase I patient study was obtained from CEIC Hospital Vall D’Hebron, PASSEIG DE LA VALL D'HEBRON S/N 119-129, 08035, Barcelona, Spain and EC/IRB Approval Date 08-Jan-2010, Hospital Clínico Universitario de Valencia; CEIC, Pabellón B. Piso 1 Avda. Vicente Blasco ibáñez, 17, 46010, Valencia, VALENCIA, SPAIN. EC/IRB Approval Date 08-Jan-2010. The Phase 1 healthy subject study was approved by Schulman Associates Institutional Review Board, Address: 4445 Lake Forest Drive, Suite 300 Cincinnati, Ohio 45242. This article does not contain any studies with animals performed by any of the authors.

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All subjects in the studies provided written informed consent prior to enrollment.

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Malhi, V., Budha, N., Sane, R. et al. Single- and multiple-dose pharmacokinetics, potential for CYP3A inhibition, and food effect in patients with cancer and healthy subjects receiving ipatasertib. Cancer Chemother Pharmacol 88, 921–930 (2021). https://doi.org/10.1007/s00280-021-04344-9

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