Tablet position in gastrointestinal tract derived from drug release measurements and plasma concentrations
Emilie HÉNIN, Martin BERGSTRAND, Mats O. KARLSSON
Department of Pharmaceutical Biosciences, Uppsala University, Sweden
Objectives: To investigate the possibility of deriving the position of a tablet in the gastrointestinal tract (GI) from drug plasma concentrations and drug release measurements.
Data: Six healthy volunteers were administered magnetically labeled extended release tablets containing felodipine, under fasting and fed conditions (1). Three types of observations were collected: tablet GI positions and drug release were monitored using Magnetic Marker Monitoring (MMM) technique, and plasma concentrations of felodipine were measured. Tablet GI position was categorized into five regions: fundus, antrum, proximal small intestine, distal small intestine and colon.
Models: Two separate models were developed to describe on one hand GI tablet transit and on the other hand GI distribution of released drug, absorption and disposition for an extended release formulation of felodipine. In the second model tablet GI position was included as an important covariate affecting both drug release, GI distribution of released drug substance and absorption rate. This model development was presented in details elsewhere (2). In this work, both models were coupled and estimated simultaneously, using prior population parameter estimates for tablet GI transit, but not the position data measured by MMM.
Beside downstream transit, GI tablet transit model enables return from antrum to fundus. This movement has been taken into account by a mixture modeling defining 3 subpopulations: no return, 1 return or 2 returns to fundus.
Prior information based on the separate modeling of the GI tablet transit data (2) was included to govern the typical value and interindividual and variability for tablet residence time in each GI region. A series of step-functions was used to describe the tablet movement from one region to the following one.
Results: Empirical Bayes Estimates for each parameter were obtained using NONMEM VI and individual tablet movement profiles were compared to observed ones. At 7 occasions, subjects were affected to the first subpopulation (no return to fundus) whereas 5 were estimated as having 1 or 2 returns to fundus, which is in agreement with observed profiles. Tablet GI positions were adequately predicted in 10 out of 12 occasions, based on the model for drug release and pharmacokinetic data, as compared to positions measured by MMM. Similar results were obtained when only plasma concentration data was used.
Conclusion: This work represents a first step in the use of prior information on GI tablet movement in absorption modeling for extended release formulations.
References:
1. Weitschies,W et al., Impact of the intragastric location of extended release tablets on food interactions. J Control Release, 2005. 108(2-3): p. 375-85
2. Bergstrand,M et al. Mechanistic modeling of a Magnetic Marker Monitoring study, linking gastro intestinal tablet transit, in vivo drug release and pharmacokinetics. Clin Pharmacol Ther (in press)
