A formulation strategy for gamma secretase inhibitor ELND006, a BCS class II compound: development of a nanosuspension formulation with improved oral bioavailability and reduced food effects in dogs.
ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimer's disease. ELND006 shows poor solubility and has moderate to high permeability, suggesting it is a Biopharmaceutics Classification System Class II compound. The poor absolute oral bioavailability of the compound in fasted dogs (F ∼11%) is attributed to poor aqueous solubility. In addition, inhibiting amyloid precursor protein but not Notch cleavage is an important goal for gamma secretase inhibitors; therefore, significant variation in bioavailability resulting from food consumption is a potential liability for this class of compounds. The objective of the present study was to determine if an ELND006 nanocrystalline formulation would offer improved and predictable pharmacokinetics. ELND006 was formulated as a nanosuspension with a mean particle size of less than 200 nm, which was stable in particle size and crystallinity for over 1 year. In addition, ELND006 nanosuspension exhibited rapid dissolution in comparison with reference active pharmaceutical ingredient (API). The in vivo performance of the ELND006 nanosuspension was tested in fed and fasted beagle dogs and compared with a gelatin capsule containing reference API. The results show that nanosizing ELND006 profoundly improved the oral bioavailability and virtually eliminated variation resulting from food intake.
Research and Development, Elan Pharmaceuticals, South San Francisco, California 94080, USA. kevin.quinn@elan.com
Kevin
K
Quinn
Rampurna Prasad
RP
Gullapalli
Elaine
E
Merisko-Liversidge
Erich
E
Goldbach
Angelina
A
Wong
Gary G
GG
Liversidge
Wherly
W
Hoffman
John-Michael
JM
Sauer
John
J
Bullock
George
G
Tonn
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001702:Biopharmaceutics; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D018565:Food-Drug Interactions; D053758:Nanoparticles / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics; D011804:Quinolines / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility; D013535:Suspensions; D014961:X-Ray Diffraction
D011480:Protease Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D013535:Suspensions; C573127:(R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo(4,3-c)quinoline; D053829:Amyloid Precursor Protein Secretases