Interspecies Pharmacokinetics Modeling of Direct Nose-to-brain DB213 Transpsort via Intranasal Administration in Mice and Rats
Refereed conference paper presented and published in conference proceedings


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AbstractPurpose
Development of interspecies pharmacokinetic models could efficiently reconcile data from different species and predict pharmacokinetic and pharmacodynamic behavior in human. Previously, we demonstrated the existence of direct nose-to-brain transport of intranasally administered DB213 (an HIV-1 replication inhibitor targeting HIV-associated neurocognitive disorders) in Sprague-Dawley rats by pharmacokinetics modeling (Fig 1). The current study aims to further evaluate the previously developed pharmacokinetic model for i) demonstration of direct nose-to-brain DB213 transport in mice; ii) investigating differences in absorption, distribution and elimination of DB213 between mice and rat.
Methods
Rats were administered with DB213 water solution via intransal or intravenous at a 1, 10 and 50 mg/kg (n=8), while mice at 25 mg/kg via intranasal (n=3-6). Plasma and brain samples were collected at 0, 15, 30, 60, 90, 120, 240, 360, 480 min post-dosing.Based on pharmacokinetic model developed in rats, several modeling iterations were evaluated for the feasibility of this model to demonstrate nose-to-brain DB213 transport in mice. First, interspecies scaling was evaluated by applying the power law equation: Pmouse=Prat×(BWmouse/BWrat) b (where P and BW represents pharmacokinetics parameters and body weight , b is an allometric exponent). Each parameter was assessed by visual predictive check of fitted curves. For evaluation of k30, k40, k34, k43, k53, k35, values of 0 and -0.25 for b were tested. The volume of the central compartment was assumed to be directly proportional to body weight. The absorption rate constants ka13, ka24 were evaluated by allometric scaling or independent fitting of mice experimental data. Model fitting and parameter estimation were performed by NONMEM (version VII).
Results
Fig 2a demonstrated the plasma/brain concentration-time profiles of intranasally delivered DB213 in mice with AUC0→480minplasma and AUC0→480minbrain of 377 ± 43 and 121 ± 19 μgm·in/ml. When the elimination rate constants k30 and k40 were scaled using an allometric exponent of -0.25 and distribution rate constants k34, k43, k53, k35 with an exponent of either -0.25 or 0, both simulations resulted in underestimation of DB213 elimination half-life in systemic circulation and brain (Fig 2b). Best DB213 elimination prediction was found when k30 and k40 were kept identical with k34, k43, k53 and k35 scaled using an exponent of -0.25 (Fig 2c). Since underestimation of absorption was observed when ka13 and ka24 were scaled with an exponent of -0.25 or 0 (Fig 2d), the estimation of ka13 and ka24 was conducted by fitting the experimental data in the model. It was noticed that the absorption rate constants were species specific with faster nose-to-systemic circulation and nose-to-brain absorption in mice than that in rats.
Conclusion
The direct nose-to-brain DB213 transport via intranasal administration existed in both mice and rats. The pharmacokinetic model successfully captured the behavior of distribution and elimination of DB213 in both mice and rat via intranasal administration.(Financial support: Lui Che Woo Institute of Innovative Medicine BRAIN Initiative)
All Author(s) ListQianwen Wang, Yufeng Zhang, Chun-Ho Wong, H.Y. Edwin Chan, Zhong Zuo
Name of Conference2017 AAPS Annual Meeting and Exposition
Start Date of Conference12/11/2017
End Date of Conference15/11/2017
Place of ConferenceSan Diego
Country/Region of ConferenceUnited States of America
Year2017
Month11
LanguagesEnglish-United States

Last updated on 2018-15-05 at 12:46