Implementation of a protocol to induce tolerance to nirogacestat in a responder patient: stability of a drinkable liquid form

Objective
Desmoid tumors are benign, non-metastatic soft tissue tumors that can be painful and hard to remove. When surgery is not feasible, treatment with the gamma secretase inhibitor nirogacestat is recommended. Our patient responded well but developed a major skin adverse effect, requiring tolerance induction with liquid formulations. A prior study showed that nirogacestat, dissolved at 2 mg/mL in ORA-SWEET^® (a compatible excipient), degraded within 48 hours, with the slowest degradation at +4°C, compared to storage -20°C and +25%. Our objective was to capture the time of the solution degradation by shortening the sampling times for nirogacestat concentrations determination.

Materials and method
After validation of a high-performance liquid chromatography diode-bar with methylclonazepam as internal standard, triplicate measurements of the content of 2mg/mL solutions were carried out at 240 nm. The mean value, in mg/L, of the 3 concentrations of an extemporaneous solution (Pex) corresponds to 100% nirogacestat. The concentrations measured over time are expressed as a percentage of this value. Deviations within -10% to +10%, are deemed to be compliant for the oral route. Two arms were explored: the first, comprising the Pex H0 (1st extemporaneous preparation made at H0, start of study), stored at +4°C, taken out a 1st time for determinations at H7 (H7), then a 2nd time for assays at H24 (H24). The 2nd arm included a new extemporaneous preparation, 7 h after Pex H0, called Pex H7, and a final extemporaneous preparation (the 3rd) 24 h after Pex H0 (Pex H24).

Results / Discussion
The average concentration (C°) of the 3 Pex solutions = 50.353 mg/L (i.e. 100% Nirogacestat). The mean C° of the 3 measurements at H7 = 88.26 mg/L (175%) and at H24 = 48.373 mg/L (96%).
The two additional extemporaneous preparations were used as controls for the operating conditions of the injection preparations on the one hand, and the separation/detection phase on the other.
At H7, the +10% threshold was exceeded. This could be due to insufficient equilibration time at room temperature before the solution was sampled.
At H24, equilibration at room temperature before injection was effective, and the mean C° was consistent with expectations.

Conclusion
It is likely that the moment of significant degradation of our Nirogacestat 2mg/mL preparation in ORA-SWEET^® occurs between 24 and 48 hours. This 24-hour stability needs to be confirmed. If confirmed, it would allow for the provision of drinkable solution that could be used for 2 consecutive days.

Keywords : drug stability ; liquide dosage forms ; gamma-secretase inhibitor

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