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

Focal adhesion kinase (FAK), also known as protein tyrosine kinase 2 (PTK2), is a non-receptor cytokine tyrosine kinase that comprises a structural component of focal adhesions. These focal adhesions are protein complexes containing cell surface integrins, which are essential for interaction with the extracellular matrix and transduction of signaling pathways [1]. FAK plays a vital role in proliferation, survival, and migration of tumor cells [2]. In cancer, dysregulation and activation of focal adhesions facilitate cell motility and promote invasive tumor growth [1]. Increased expression of FAK is found in various tumor types, and the extent of expression has been related to the extent of disease progression and metastasis [3]. In particular, FAK overexpression has been implicated in the development of sarcomas, and prostate, colorectal, ovarian, and breast cancer [4‐9].

In mice, genetic knockout of FAK has been shown to be embryonically lethal, underscoring its role in development, particularly in the formation of blood vessels [10]. Chemical inhibition of FAK has been shown to reduce FAK activity and block tumor growth in a range of xenograft models [11‐14]. Moreover, inhibition of FAK on endothelial cells has been shown to improve sensitivity of tumor cells to chemotherapy and immunotherapy in preclinical models [15, 16]. Several inhibitors of FAK have been evaluated in patients with cancer [17‐19], both as monotherapy and in combination with chemotherapy, targeted and immune therapies [20]. BI 853520 is a potent inhibitor of FAK, and clinical exploration has shown target engagement and anti-tumor activity in the phase I studies reported by de Jonge et al. [21] and Doi et al. [22] in this issue of Targeted Oncology. In the study by de Jonge et al. [21] involving primarily Caucasian subjects who were dosed in the fasted state, BI 853520 was rapidly absorbed and exhibited at least biphasic disposition kinetics. BI 853520, which is classified as a class 1 drug in the Biopharmaceutics Classification System (BCS), was orally bioavailable, with an observed terminal half-life (t_½) of 19 h following administration of a single dose, supporting a once-daily dosing schedule.

A major determinant of drug absorption is the impact of concomitant administration with or without food [23]. Food, among other factors, may influence gastric pH, emptying, and motility. Moreover, the presence of a high-fat meal may improve the solubility of lipophilic drugs, thereby increasing (relative) bioavailability. All of these factors can influence the rate and extent of gastrointestinal absorption and indicate the need to study the effects of food on drug bioavailability during clinical drug development [24, 25]. A marked influence of food on absorption has been reported for several orally dosed anti-cancer drugs [26‐29]. In particular, in the case of abiraterone, a 1000% increase in the area under the plasma concentration–time curve (AUC) was demonstrated when the drug was administered with food compared to a fasted state, illustrating a clinically relevant food effect [27].

The requirement to administer drugs in the fasting state can have a major impact on patients’ well-being, especially if the fasting state has to be continued for several hours after drug administration. Further, oral administration of drugs can be problematic for those who cannot swallow whole tablets. This may be particularly relevant in patients with some advanced cancers such as head and neck cancer or esophageal cancer. Therefore, development of an alternative oral formulation could increase the convenience of administration for patients. However, any alternative formulation should be tested clinically first to demonstrate that it achieves appropriate pharmacokinetic exposure.

We report on two randomized, open-label, crossover studies evaluating the effect of administration with or without a high-calorie meal, and the effect of administration as a liquid dispersion on the pharmacokinetics of the novel FAK inhibitor BI 853520. These pharmacokinetic studies were part of a larger phase I dose-finding trial.

In total, 16 patients were enrolled in each study; patient characteristics are presented in Table 1. In the food-effect study, 15 patients were evaluable for treatment in at least one state (fed or fasted), and one plasma concentration–time profile was excluded for one patient due to vomiting after drug administration. In the liquid–tablet study, all 16 patients were evaluable for treatment with at least one dose (liquid or tablet) of BI 853520, and one plasma concentration–time profile was excluded for one patient due to incomplete drug administration.

The possible effects of food and formulation (liquid dispersion vs. tablet) on pharmacokinetic parameters of BI 853520 were assessed in two randomized, open-label, crossover pharmacokinetic studies. A total of 16 patients were planned for enrollment in each study. This planned sample size was not based on a power calculation, but was judged to be appropriate to achieve the aims of this exploratory substudy, and as being adequate to provide a minimum of 12 evaluable patients for the analysis, as required by FDA guidance.

The plasma profile, t_max and t_½ of BI 853520, when taken after a high-calorie meal, were not markedly different from those in fasted patients. The 90% CI for the adjusted GMRs for \({\text{AUC}}_{{0{-}t_{\text{z}} }}\), AUC_0–∞,obs, and C_max all crossed the lower of the 80–125% boundaries. However, we do not consider the reductions to result in clinically meaningful differences in exposure. Our data, therefore, seem to support the view that BI 853520 may be administered orally without the need for stringent conditions regarding food intake. Interestingly, the geometric mean value for C_max decreased slightly when BI 853520 was administered with food (Table 2), while the median value increased (Fig. 3).

Administration of BI 853520 after dispersion of the tablet in a reconstitution solvent did not appear to have any clinically important impact on the measured pharmacokinetic parameters. None of the 90% CIs of the calculated pharmacokinetic parameters crossed the predefined 80–125% limits. This suggests that the bioavailability of BI 853520 is not strongly affected by liquid dispersion and supports the use of the reconstitution liquid to facilitate drug administration in patients who have problems swallowing.

Overall, the results of our study suggest that the pharmacokinetic profile of BI 853520 is unlikely to be greatly influenced by concomitant administration with food or the type of formulation. These properties should allow for a patient-friendly posology, without strict requirements for administration under fasted conditions. In addition, administration of BI 853520 as a liquid dispersion may be particularly convenient for patients who experience problems swallowing.

As is apparent from Fig. 3, we observed large inter-individual pharmacokinetic variability in our study; this was also observed in the dose-finding study (see de Jonge et al. [21]). This variability cannot yet be explained; however, it may relate to differing plasma levels of α-1-acid glycoprotein (AGP), the major binding partner of BI 853520 in human plasma.

These randomized, open-label, crossover studies suggest that a high-calorie meal did not appear to have a large impact on BI 853520 pharmacokinetics. Further, our data suggest that the formulation of BI 853520 as a liquid dispersion has no important effects on the pharmacokinetics of BI 853520 relative to the tablet formulation. These pharmacokinetic properties may help make BI 853520 dosing more convenient and flexible, improving treatment compliance.