Relative bioavailability of three formulations of galunisertib administered as monotherapy in patients with advanced or metastatic cancer

Relative bioavailability of three formulations of galunisertib administered as monotherapy in patients with advanced or metastatic cancer

Article Details

Authors
Ivelina Gueorguieva, Ann Cleverly, Durisala Desaiah, Analia Azaro, Joan Seoane, Irene Braña, Elisabet Sicart, Colin Miles, Michael M Lahn, Malcolm I Mitchell, Jordi Rodon

Article Type
Original Research

DOI
10.7573/dc.212303

Related Articles

Article Page

Abstract 

Objective: Galunisertib (LY2157299 monohydrate), an inhibitor of the transforming growth factor β (TGFβ) pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC) dry-milled (RCD) and RC slurry-milled (RCS) processes, compared with the existing formulation developed using the high-sheer wet granulation (HSWG) process. The secondary objective was to report the safety profile after a single dose of the three formulations.

Methods: Patients with advanced or metastatic cancer were enrolled into this single-center, 3-period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK) parameters, including area under curve (AUC) and Cmax, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and Cmax values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests.

Results: Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-tlast), AUC(0-48 h), and AUC(0-∞) for the RC formulations and the HSWG formulation were similar. Cmax was reduced by approximately 22% and tmax was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation.

Conclusions: In this relative bioavailability study comparing galunisertib formulations after a single dose, RCD and RCS formulations had similar exposure and safety profile compared with the HSWG formulation.

Keywords: LY2157299, transforming growth factor beta, area under curve, biological availability, half-life, pharmacokinetics, neoplasms, adverse drug event.

Abbreviations: AE, adverse events; API, active pharmaceutical ingredient; AUC, area under curve; Cmax, maximum plasma drug concentration; CI, confidence interval; CTCAE v3.0, common terminology criteria for adverse events version 3.0; CV, coefficient of variation; ECOG, Eastern Cooperative Oncology Group; FHD, first-in-human dose; HSWG, high-sheer wet granulation; ICD, informed consent declaration; LC/MS, liquid chromatography/mass spectrometry; LSM, least squares mean; PD, pharmacodynamics; PK, pharmacokinetic; PS, performance status; RBA, relative bioavailability; RC, roller compaction; RCD, roller compaction dry-milled; RCS, roller compaction slurry-milled; SAE, serious adverse events; TEAEs, treatment-emergent adverse events; TGFβ, transforming growth factor β

Citation: Gueorguieva I, Cleverly A, Desaiah D, Azaro A, Seoane J, Braña I, Sicart E, Miles C, Lahn MM, Mitchell MI, Rodon J. Relative bioavailability of three formulations of galunisertib administered as monotherapy in patients with advanced or metastatic cancer. Drugs in Context 2016; 5: 201303. DOI: 10.7573/dic.212303.

Disclosure and potential conflicts of interest: Dr. Rodon has served as consultant on Eli Lilly advisory boards and received financial compensation. Drs. Azaro, Seoane, Brana, and Sicart have no conflict of interest. Dr. Gueorguieva, Dr. Desaiah, Mr. Miles, and Ms. Cleverly are employees of Eli Lilly and Company, Indianapolis, IN, USA and Erl Wood, UK and may hold company stocks. Drs. Lahn and Mitchell were former employees of Eli Lilly and Company and may hold company stock. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors are available for download at: http://www.drugsincontext.com/wp-content/uploads/2016/12/dic.212303-COI.pdf.

Acknowledgements: Sriram Govindan, PhD, an employee of Eli Lilly provided medical writing assistance for this manuscript. The authors would like to thank James A. Wesley and David C. Sperry, both employees of Eli Lilly, for their advice on the formulations used in the study. The authors would like to thank all patients and all the site staff for their participation in the study.

Funding declaration: The study was sponsored by Eli Lilly and Company, IN, USA.

ClinicalTrials.Gov: NCT01682187

Copyright: Copyright © 2016 Gueorguieva I, Cleverly A, Desaiah D, Azaro A, Seoane J, Braña I, Sicart E, Miles C, Lahn MM, Mitchell MI, Rodon J. Distributed under the terms of the Creative Commons License Deed CC BY NC ND 3.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Correct attribution: Copyright © 2016 Gueorguieva I, Cleverly A, Desaiah D, Azaro A, Seoane J, Braña I, Sicart E, Miles C, Lahn MM, Mitchell MI, Rodon J. http://doi.org/10.7573/dic.212303. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 3.0.

Article URL: http://www.drugsincontext.com/relative-bioavailability-of-three-formulations-of-galunisertib-administered-as-monotherapy-in-patients-with-advanced-or-metastatic-cancer

Correspondence: Ivelina Gueorguieva, PhD, Principal Research Scientist, Global PK/PD, Pharmacometrics, Eli Lilly and Company, Erl Wood, UK. gueorguieva_ivelina@lilly.com

Submitted: 21 September 2016; Peer review comments to author: 20 October 2016; Publication date: 2 December 2016

Drugs in Context is published by Bioexcel Publishing Ltd. Registered office: 14 Weller Street, London, SE1 1QU, UK

Bioexcel Publishing Limited is registered in England Number 10038393. VAT GB 252772009

For all manuscript and submissions enquiries, contact Julia Savory, Head of Digital Publishing and Submissions Management
julia.savory@bioexcelpublishing.com

Download free full text PDF

Resources