2008 - Marseille - France

PAGE 2008: Lewis Sheiner Student Session
Martin Bergstrand

Modeling of gastro-intestinal tablet transit and its’ effect on drug release and absorption for felodipine extended release tablet under fed or fasting conditions

Martin Bergstrand (1), Erik Söderlind (2), Mats O Karlsson (1)

(1) Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.; (2) Product Development, AstraZeneca R&D Mölndal, Sweden

Background: Magnetic Marker Monitoring is a novel technique for visualising the transit of a solid oral dosage form through the GI tract. For dosage forms with erosion controlled drug release, the technique can also be used for obtaining an in-vivo drug release profile [3].

Aim: A model capable of simulating gastro intestinal transit, in vivo drug release and absorption of felodipine extended release tablet under fed or fasting conditions.

Methods: In a clinical crossover study the gastrointestinal transit and the in-vivo drug release of magnetically labeled extended release tablets containing felodipine were monitored under fasting and fed conditions in six healthy volunteers using Magnetic Marker Monitoring [4]. Observations from this study were of three kinds: GI location of the tablet, remaining non-disintegrated tablet and plasma concentration of felodipine.

An integrated mechanistic model describing in-vivo drug release and plasma concentration was constructed. Tablet GI position was included in the model as a covariate, governing the turning on and off drug release into corresponding absorption compartments. The systemic distribution of felodipine was described by a central observation compartment and two peripheral compartments. This part of the model was parameterized with clearance and volume parameters and allometric scaling is assumed a priori for all parameters [2]. NONMEM VI, FOCE I, was used for estimation of model parameters.

The transit between the distinct GI positions; fundus, antrum, proximal small intestine, distal small intestine and colon was described by a separate markov chain model. Since observations were made with varying frequency differential equations and first order rate constants were used to describe change in tablet GI position probability. The markov principle was kept by re-initializing all compartment amounts after each observation. NONMEM VI, LAPLACIAN LIKE, was used for estimation of all markov model parameters.

Results and Discussion: The in vivo drug release was best described with three different zero order rate constants depending on the position of the non-disintegrated tablet. A relatively slow release rate was seen for fundus (D1). An approximately three times faster release rate was estimated for antrum and the proximal small intestine (D2/D3). In the distal part of the small intestine and colon the drug release rate was estimated to be intermediate in comparison to D1 and D2/D3. The interindividual variability for the different rate constants was highly correlated and sufficiently described with only one variability term affecting all rate constants. The magnitude of the interindividual variability was also seemingly small, 9%.

Mixing of gut content in fundus is low which is manifested in the model by a slow first order distribution constant for released drug content passing down to the distal stomach (K23). As the tablet moves down to the distal part however, it is likely that released drug in the proximity of the tablet is also moved in a sudden fashion. This effect has been incorporated in the model. The distribution rate from distal stomach to small intestine (K34) was estimated to be considerably faster than K23 but showed the same pattern in terms of acceleration after tablet movement. Absorption can be rate limited by either dissolution or permeability. An observed three-fold faster absorption rate in small intestine (K47 and K57) compared to colon (K67) is thought to be due to a lower dissolution rate in colon. It was hypothesized during the model development that the pre-hepatic bioavailability (FA) might differ over the different GI parts, however no such significant effect was detected.

The model suggests that food intake decreases the rate with which released drug substance in the distal stomach is passed down to the stomach (K34 -70 %) and increases pre-hepatic bioavailability (FA +70 %).

In the markov model describing GI transit the tablet can move back and forward between the upper and lower part of the stomach (fundus and antrum). The probability of transiting through out the proximal small intestine is described by four transit compartments (P:1- P:4). Transit through out the distal part is similarly described by three transit compartments (D:1 D:3). In the model colon is assumed to be a final stage from which the tablet moves no further. Concomitant food intake prolongs the tablet stay in the stomach by decreasing probability of moving from fundus to antrum and from antrum to small intestine.

The model predicts a median time of gastric emptying at approximately 45 min for tablets taken in a fasting state. The corresponding time for the fed state is 4 hr and 45 min. Tablet transit from antrum to fundus is approximately ten times more probable when the table is taken together with food. On average this movement occurs once following each tablet intake together with food. Furthermore that model predicts a median time of colon arrival of 4.25 hr and 8.5 hr after fasting respectively fed tablet intake.

Conclusions: The joint information in tablet GI location, in-vivo drug release and plasma concentration can be utilized in a mechanistically informative way with integrated modeling of data from Magnetic Marker Monitoring studies.

[1] Edgar, B., et al., Felodipine kinetics in healthy men. Clin Pharmacol Ther, 1985. 38(2): p. 205-11.
[2] Holford, N.H., A size standard for pharmacokinetics. Clin Pharmacokinet, 1996. 30(5): p. 329-32.
[3] Weitschies, W., et al., Magnetic Marker Monitoring: An application of biomagnetic measurement instrumentation and principles for the determination of the gastrointestinal behavior of magnetically marked solid dosage forms. Adv Drug Deliv Rev, 2005. 57(8): p. 1210-22.
[4] 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.

Reference: PAGE 17 (2008) Abstr 1265 [www.page-meeting.org/?abstract=1265]
Oral Presentation: Lewis Sheiner Student Session