Category: Preclinical Development
Purpose: At the current time there are no less than 30 companies in non-clinical and clinical development of therapeutics for delivery to the brain via nasal deposition. There is a paucity of peer reviewed literature describing non-clinical models to evaluate nose-to-brain drug delivery. Therefore, a non-clinical model has been developed in non-human primates (NHP) to deliver therapeutics systemically and intranasally (liquid and dry powders), collect serial blood and cerebrospinal fluid (CSF) samples and perform quantifications for the model compound. The model will enable the ability to quantify differences in nose to brain delivery in a non-clinical in vivo setting.
Methods: LCMS methods were developed to quantify sumatriptan from systemic plasma and CSF. The methods were developed with samples volumes (100 μL plasma and 50 μL CSF) that enable serial collection for pharmacokinetic analysis. A non-terminal cross over study in cynomologus macaques (age 6-10 years ~ 3.5 kg) was conducted with dry powder nasal delivery (Aptar Unit Dose Powder device, 10 mg dose), liquid aerosol delivery (Imetrex in Aptar Unit Dose device, 10 mg dose) and subcutaneous (SubQ) injection (Imetrex, 0.1 mg/kg). CSF was collected via cisternal puncture at 7 timepoints out to 4 hours. Blood was collected via venipuncture at 8 timpoints out to 8 hours. Samples were assayed via the developed LCMS assays. A non-compartmental analysis (NCA) was performed (WinNonlin) to quantify the Tmax, Cmax, AUC, half-life and bioavailability in each matrix.
Results: The fit for purpose LCMS methods supported quantification ranges of 0.1 – 100 ng/mL in plasma and 0.5 to 500 ng/mL in CSF. The nasal delivery, for both devices, was well adapted to the NHP without modification. The delivery of SubQ and both intranasal formulations was completed without any observed adverse events and all samples were collected for each dose group without issue. The concentration vs. time profiles are shown in Figures 1 and 2. The NCA showed that the nasal powder resulted in increased AUC and Cmax and reduced Tmax compared to the aqueous nasal spray and the SubQ injection. Additionally, the nasal dry powder resulted in increased plasma bioavailability.
Conclusion: These data support the use of the NHP as a non-clinical model to evaluate nasal drug delivery, and suggest that the nasal powder may have resulted in direct nose to brain delivery. The cause of the increased exposure from the nasal dry powder is not specifically known. However, it is speculated that the dry powder may have deposited in the nasal cavity and been retained at the site of deposition to a greater degree than the nasal spray. Previous studies have shown that nasal sprays can result in the delivered formulation dripping down the outside of the nares or into the throat (Leach, et. al., J. Aerosol Med., 28(5), 2015) and therefore this may have contributed to the differences seen within this study.
Meghan Vermillion– Albuquerque, New Mexico
Edward Barrett– Albuquerque, New Mexico
Jason Cox– Albuquerque, New Mexico
Badre Hammond– Crystal Lake, Illinois
Larry Mallis– Albuquerque, New Mexico
Bianca Myers– Albuquerque, New Mexico
Karin Rudolph– Albuquerque, New Mexico
Tyler Sniegowski– Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Julie Suman– Baltimore, Maryland
Gerallt Williams– Le Vaudreuil, Rhone-Alpes, France