H. T’jollyn(1), J. Vercruysse(2), E. De Thaye(1), J.P. Remon(2), A. Vermeulen(1), J. Van Bocxlaer(1), C. Vervaet(2)
(1) Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University, Belgium; (2) Laboratory of Pharmaceutical Technology, Ghent University, Belgium
Objectives:
- Develop a population PK model to describe plasma and brain pharmacokinetics of galantamine (Gal) in rabbits after intranasal delivery.
- Compare bioavailability and rate of absorption between different formulations with varying composition.
- Investigate direct nasal-to-brain transport of Gal.
Methods: For 10 different single dose formulations (intravenous and intranasal), blood was sampled from the rabbit’s ear vein pre-dose and at 8 time points post-dose. For the multiple dose (MD) study, one intranasal formulation was selected and administered every hour for 5 consecutive doses. Plasma concentrations for every rabbit were measured after the first dose and then alternately after consecutive doses. Brain data were collected at every trough level, and around Tmax after the 4th dose. A nonlinear mixed-effects pharmacokinetic model was developed in NONMEM 7.2.0 (Icon Development Solutions, Ellicott City, MD, USA) using the first-order conditional estimation method to describe Gal disposition in plasma and brain. Distribution to the brain was assumed to take place from the central compartment, and was described using micro-constants. The volume of the brain was fixed to a wet tissue weight of 12g [1].
Results: A two-compartment model with first-order absorption and elimination best described the plasma PK of Gal. Depending on the formulation’s properties, distinct plasma concentration-time profiles were obtained, mainly resulting from differences in bioavailability (range 52-100%) and nasal rate of absorption (rate constant range 0.046-1.86 min-1). In addition, the absorption rate of pure Gal base was 17 times that of pure Gal HBr powder. For the investigation of the direct nasal-to-brain transport, several structural models were tested, but none was supportive of a direct nasal-to-brain process, in contrast to earlier findings in the rat [2].
Conclusions: Gal absorption after intranasal administration differed markedly between formulations and was highest and fastest after administration of pure Gal base powder, without excipients. Extended release times can be obtained by using Amioca®/Carbopol®:API (ratio 90/10). Gal transfer from plasma to brain is the rate limiting step in its brain distribution, with no indications for a direct nasal-to-brain route in rabbits.
References:
[1] MSTE data archive. MSTE Data Archive: Body and Brain Weights. [cited 05-05-2015]; Available from: http://mste.illinois.edu/malcz/DATA/BIOLOGY/Animals.html
[2] Stevens J, Ploeger BA, van der Graaf PH, Danhof M, de Lange EC. Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration. Drug Metab Dispos. 2011 Dec;39(12):2275-82
Reference: PAGE 25 (2016) Abstr 5835 [www.page-meeting.org/?abstract=5835]
Poster: Drug/Disease modeling - Absorption & PBPK