XS003, an amorphous re-formulation of nilotinib, demonstrates improved dose linearity and minimal food effect, reducing the risk of QT-prolongation at fed conditions

Abstract Background: Crystalline formulated nilotinib (Tasigna®) is an established tyrosine kinase inhibitor benefiting patients with chronic myeloid leukemia. Nilotinib may, however, cause QT-prolongation and thereby trigger life-threatening ventricular arrhythmias. The relationship between QT-prolongation and nilotinib serum concentrations is estimated to 9 ms per 1000 ng nilotinib/mL. Crystalline nilotinib exhibits poor dose-exposure linearity due to limitations in solubility and render Cmax to increase more than 2-fold (112%) when administered with a high-fat meal. Consequently, to mitigate the risk of serious cardiac arrythmias, crystalline nilotinib must not be taken with food, enforcing fasting before and after drug intake. A reformulation of nilotinib could potentially reduce unwanted food interaction effects, and multiple bioequivalent (BE) nilotinib formulations have recently been put forward. However, significant non-linear exposure between dose levels appears to persist. XS003 nilotinib (XS003) (Xspray Pharma, Solna, Sweden) is an amorphous solid dispersion (ASD) formulation, produced using the HyNap technology to enhance oral bioavailability. Here we report on the establishment of BE of XS003 with crystalline nilotinib, dose-exposure linearity and food effect on nilotinib exposure when administered as XS003. Methods: BE between XS003 (144 mg and 192 mg) and crystalline nilotinib (300 mg and 400 mg) was established via a two-compartment Population PK steady-state model (popPK) with linear elimination for nilotinib based on a single-dose study with XS003 (4x48 mg) and crystalline nilotinib (400 mg). An in silico continuation approach was applied after having carefully and accurately fitted individual subject data from the clinical study of 123 healthy subjects and simulated. Bioequivalence was considered if at least 90% of all simulated studies met the standard criteria of 80.00%-125.00%. The food effect on XS003 was investigated in 48 healthy subjects in a randomized, two-period, two-sequence, single dose, cross over study. XS003 capsules (4x48 mg nilotinib) were administered under fasted and fed (high-fat meal) conditions. 90% confidence intervals (CI) of geometric mean ratios of Cmax and AUC0-twere used to assess BE under fasted and fed conditions. Subjects were monitored for AEs (according to CTCAE v5.0). Safety parameters, including laboratory results, physical examination, vital signs and 12-lead electrocardiogram, were assessed throughout the conduct of the study. Using results from the study, steady state PK was estimated using PopPK modeling. Results: BE was demonstrated at both investigated dose levels of XS003 (144 mg and 192 mg) and crystalline nilotinib (300 mg and 400 mg), respectively, with 90%CIs within 80.00% and 125.00%. In the PopPK model, crystalline nilotinib exposure increased by 47% (AUC) between 300 mg and 400 mg, whereas XS003 exposure increased by 78% between the two doses (144 mg and 192 mg), indicating a non-linear dose-exposure with crystalline nilotinib and a near dose proportional exposure with XS003. Nilotinib Cmax and AUC0-tratios with XS003 dosing in fed and fasted state were 84% and 129% respectively, translating to a decrease of 16% of Cmax and an increase of 29% AUC0-t in the fed state. Cmax in fed and fasted state were 880 ng/mL and 1053 ng/mL, respectively (90%CI: 73,0;95,7), thereby demonstrating a lack of clinically relevant effect of food. At steady state, when administered in the fed state Cmax of XS003 (192 mg nilotinib) was estimated to 1684 ng/mL, compared to 2911 ng/mL with crystalline nilotinib (400 mg). Conclusion: XS003 was BE to crystalline nilotinib at 52% lower dosages. The impact of food intake on nilotinib bioavailability and systemic exposure when administered as XS003 (192 mg ASD nilotinib) was minimal. Furthermore, its dose-exposure was near proportional and clearly superior to that of crystalline nilotinib. In addition, compared to other BE nilotinib re-formulations, XS003 appears to provide the most limited food-related influence on nilotinib bioavailability and the highest dose-exposure linearity. The combined properties of XS003 may enable food-independent nilotinib administration with a diminished risk of concentration-dependent adverse events, including QT-prolongation and reduce cardiovascular risk. This can further improve patient safety, wellbeing and treatment outcome in CML.