Bioequivalence Study Results Showcase Reduced Variability With Dasatinib ASD Formulation

Leif Stenke, MD, PhD

The TKI dasatinib (Sprycel) is formulated as a crystalline dasatinib monohydrate. As such, the agent has a low and pH-dependent solubility with highly variable intestinal absorption and plasma pharmacokinetics, according to Leif Stenke, MD, PhD. Using an amorphous solid dispersion (ASD) formulation, investigators hypothesized that this variability would be reduced, and the bioavailability would be improved.

XS004 dasatinib (XS004), administered as 100 mg dasatinib ASD, was compared with the reference product of 140 mg dasatinib nonASD. In a poster presented at the 2022 ASH Annual Meeting, investigators wrote, “XS004 displayed a more robust and consistent [gastrointestinal] GI absorption and bioavailability, with significantly reduced intra- and intersubject variability in plasma dasatinib concentrations, compared [with] the original nonASD (crystalline)-formulated dasatinib.”¹ Authors expect that the improved biopharmaceutical properties may reduce the potential for risk of adverse effects and increase the efficacy of dasatinib within the therapeutic window.²

In an interview with OncLive^®, Stenke, an adjunct professor at the Karolinska University Hospital and Karolinska Institutet in Solna, Sweden, discussed the nuances of the 2 formulations, and the role XS004 may have in future clinical development.

OncLive^®: What are some of the chemical and clinical downsides of the current formulation of dasatinib in CML?

Stenke: A clear downside is the dependence on pH in the GI tract, in particular the stomach. Comedication with any agent that influences the gastric pH might also influence the intestinal uptake of TKIs. In our presentation [at 2022 ASH], we focus on the comedication between the TKI dasatinib and proton pump inhibitors, as these [drug-drug] interactions are of clinical concern.

There is recommendation from the FDA against using [a TKI], in this case dasatinib, together with proton pump inhibitors because of these interactions affecting the intestinal uptake and systemic exposure of the active drug—that is a clinical concern. In addition, the [high] variation in bioavailability can present the problem with TKIs. Some will have an extensive as well as a low uptake, leading to patients being under and over exposed to crystalline dasatinib. With this new formulation, we believe that this problem can be minimized.

Please provide some context on the distinguishing factors of ASD.

[Referencing my colleagues, I can say XS004] is an improved solubility of an amorphous dasatinib and that leads to increased bioavailability and reduced dependency on the pH. It is manufactured through a new pharmaceutical technology—HyNap—where amorphous dasatinib is embedded in the [carrier] matrix…with the higher solubility and dissolution rate compared with the nonASD formulations that are currently on the market.

[The] polymer in the compound XS004 stabilizes thermodynamically unstable dasatinib ASD and acts as a polymeric precipitation inhibitor for the dissolved dasatinib. The in vitro solubility and in vivo pharmacokinetic data provide the evidence, that this ASD formulation maintains long-lasting supersaturated states of dissolution of dasatinib in the GI lumen by preventing precipitation. That’s the pharmacological language around this new oral product XS004.

What did the results show in the comparison between XS004 and dasatinib?

My colleague, Hans Lennernäs, PhD, [of Uppsala University in Sweden] who presented this poster [described] that XS004 100 mg demonstrated equivalence in plasma exposure, increased bioavailability, and reduced intra- and inter-individual variability compared with crystalline dasatinib 140 mg.¹

We then looked at 140 mg of crystalline dasatinib vs 100 mg of XS004. The absorption of XS004 was less affected by GI factors such as luminal pH, gastric emptying, and fluid volume. The reduced plasma pharmacokinetic variability leads to more predictable plasma concentrations and allows for drug intake more independent of food or concomitant use of acid-reducing agents, such as proton pump inhibitors.

XS004 has improved properties that can ensure a reliable total exposure above defined cutoff value as avoiding high traffic exposure that is known to be related to pleural effusion. Taken together, XS004 is expected to improve safety, perhaps clinical outcome, and the daily life for patients in need of dasatinib treatment.

What do you believe are the next steps for this agent or class of agents altogether?

The FDA has granted XS004 orphan drug designation [for] the treatment of [chronic myeloid leukemia] CML [and Ph-positive acute lymphoblastic leukemia]. XS004 is under FDA review for market approval under the 505(b)(2) new drug application regulatory pathway.²

Is there anything else clinicians should know about this study or agent?

As a clinician treating patients with CML, we’ve seen tremendous improvements in survival, but this disease is now a chronic disease requiring in [most] patients constant and long-term TKI treatment. It’s important that we try to improve the tolerability and the outcomes for these patients, so more individuals can reach what we call treatment-free remission. On this path to improve the outcomes, what XS004 seems to offer is of importance and may benefit more patients in the future.

References

1. Lennernäs H, Liljebris C, Brisander M, et al. XS004 dasatinib (XS004) improves variability and bioavailability in humans using amorphous solid dispersion formulation of dasatinib with implications for its clinical use. Blood. 2022;140(suppl 1):9652-9653. doi:10.1182/blood-2022-169884
2. Xspray presents novel scientific data for XS004 in the chronic myeloid leukemia (CML) session at the 2022 Meeting of the American Society of Hematology. News release. Xspray Pharma AB. December 13, 2022. Accessed December 14, 2022. bit.ly/3PqIwLF