Randomized, Open-Label, Crossover Studies Evaluating the Effect of Food and Liquid Formulation on the Pharmacokinetics of the Novel Focal Adhesion Kinase (FAK) Inhibitor BI 853520

Abstract

Background: BI 853520 is a potent inhibitor of focal adhesion kinase and is currently under clinical development for the treatment of non-hematological malignancies.

Objective: The objective of this study was to evaluate the effect of food and liquid dispersion on the pharmacokinetics of BI 853520 in two open-label, crossover substudies.

Patients and methods: Sixteen patients with advanced solid tumors were enrolled in each substudy. The order of administration was randomized, and pharmacokinetic samples were collected for 48 h after administration of a 200 mg dose of BI 853520. Lack of effect would be demonstrated if the 90% confidence interval (CI) of the ratio of the adjusted geometric mean (GMR) of the area under the plasma curve (area under the plasma concentration-time curve from time zero to the last quantifiable concentration at tz [[Formula: see text]] and observed area under the plasma concentration-time curve extrapolated from time zero to infinity [AUC0-∞,obs]) and maximum plasma concentration (Cmax) did not cross the 80-125% (bioequivalence) boundaries.

Results: Adjusted GMRs (90% CIs) for the fed versus fasted state were 92.46% (74.24-115.16), 98.17% (78.53-122.74), and 87.34% (71.04-107.38) for [Formula: see text], AUC0-∞,obs, and Cmax, respectively. Although the 90% CIs were not within bioequivalence limits for the food-effect study, the limited reductions in these pharmacokinetic parameters after administration with a high-fat meal are unlikely to be clinically relevant. Compared with a tablet, administration of BI 853520 as a liquid dispersion did not strongly affect [Formula: see text], AUC0-∞,obs, or Cmax, resulting in adjusted GMRs (90% CIs) of 1.00 (0.92-1.09), 0.98 (0.90-1.07), and 0.93 (0.86-1.01), respectively.

Conclusions: These studies demonstrate that BI 853520 can be given with no food restrictions, and as a liquid dispersion, without strongly impacting pharmacokinetics. These pharmacokinetic properties may help make BI 853520 dosing more convenient and flexible, improving treatment compliance.

Clinical trials registration: ClinicalTrials.gov identifier: NCT01335269.

Conflict of interest statement

Remy B. Verheijen is an employee of AstraZeneca. Lillian L. Siu reports clinical trial funding (for her institution) for this study provided by from Boehringer Ingelheim. Linda C. Pronk and David Schnell are employees of Boehringer Ingelheim. Filip Y. F. L. De Vos has been paid for expert testimonial by Bristol-Myers Squibb, and received grants from Novartis. Hal W. Hirte has received honoraria from AstraZeneca, Roche, and Merck. Diane A. J. van der Biessen, Sebastien J. Hotte, Anna Spreafico, Maja J. A. de Jonge, Neeltje Steeghs, and Martijn P. Lolkema declare no conflicts of interest.

Figures

Fig. 1

Schematic of randomized, open-label, crossover trials to evaluate the effect of food and formulation on the pharmacokinetics of a 200 mg dose of the focal adhesion kinase (FAK) inhibitor BI 853520. The order of administration [fasted–fed vs. fed–fasted (a) or tablet–liquid vs. liquid–tablet (b)] was randomized (R), and a washout period of 1 week applied between the two treatments. After the pharmacokinetic studies, patients continued on a daily dose of 200 mg of BI 853520 (as a tablet) until disease progression, intolerability of the study medication, or withdrawal of consent

Fig. 2

Plasma concentration–time curves for BI 853520 (200 mg) in the food-effect and liquid formulation studies. Mean plus standard deviation of the plasma concentration–time curves for a 200 mg BI 853520 tablet administered to patients in a fed and fasted state (a) and a 200 mg dose of BI 853520 administered as a liquid dispersion and tablet (b)

Fig. 3

AUC0–48, AUC0–∞,obs, and Cmax of BI 853520 (200 mg) in the food-effect and liquid formulation studies. Boxplots of AUC0–48, AUC0–∞,obs, and Cmax of BI 853520 following a single 200 mg dose administered as a liquid or tablet in the liquid formulation study, and under fed or fasted conditions (both as a tablet) in the food effect study. AUC0–∞,obs observed area under the plasma concentration–time curve extrapolated from time zero to infinity, AUC0–48 area under the plasma concentration–time curve from time zero to 48 h, AUC0-tz area under the plasma concentration–time curve from time zero to the last quantifiable concentration at tz, Cmax maximum plasma concentration