Emilie Hénin, Mats O. Karlsson
Department of Pharmaceutical Biosciences, Uppsala University, Sweden
Objectives: To investigate a semi-physiological model approach to describe drug absorption kinetics when only plasma concentrations are available.
A similar approach based on Marker Magnetic Monitoring (MMM) studies was presented elsewhere[1]: individual tablet movement and plasma concentration profiles could be predicted correctly, without using tablet position measurements, but population estimated parameter distributions from MMM modeling.
The aim of this work is to apply a relatively complex model structure accounting for a priori knowledge on tablet transit through gastrointestinal tract (GI) to an example were MMM measurements were not performed.
Patients & Models: The model has been developed from a previously proposed model for GI tablet movement[2] and a separately developed diclofenac disposition model. The two models were linked by an absorption model in order to predict simultaneously tablet position in GI tract and diclofenac plasma concentration. The discrete movement of tablet has been translated into step functions, where each position (fundus, antrum, proximal small intestine, distal small intestine and colon) corresponds to specific absorption characteristics. It has also been assumed that tablet GI transit times remained unchanged across drugs.
30 healthy adult volunteers were administered 50mg diclofenac under fasting conditions in a bioequivalence study[3]; two formulations were compared, entero-coated tablet and suspension. Samples were taken at 0.25, 0.5, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 9, and 12h after administration. The semi-physiologic approach has been applied to diclofenac entero-coated data.
Diclofenac disposition was estimated from intravenous pediatric data[4], and well characterized by a bi-exponential elimination, with parameters scaled to weight. In our approach, disposition parameter distributions were fixed to population estimates, and total bioavailability and absorption rates for each GI region were estimated using NONMEM 7.
Results: After transit intact through stomach (fundus + antrum), the tablet sequentially moves to proximal small intestine, distal small intestine, and colon. The transit through stomach was estimated to take 2 hours in average (ranging from 35 min to 3.5 hours across the studied individuals). Compared to a more empirical model, the applied approach with prior information on tablet movement and location was able to better characterize the large variability in lag-time before diclofenac systemic uptake.
Absorption was estimated to occur mainly in the distal small intestine, and to a smaller extent in the proximal small intestine. Most of the dose was absorbed before the remaining tablet reaches the colon. Total bioavailability was estimated to be 65%, which is in accordance with values reported in the litterature.[5]
Conclusion: We were able to estimate different absorption rates for different GI regions, accounting for a priori knowledge on tablet movement through GI tract.
An integrated PK model for absorption, drug release, GI transit and disposition will aim to discriminate between system-, drug- and formulation- specific parameters. Semi-physiological approaches integrate higher complexity, which can be valuable to better capture complex phenomena, such as drug absorption. However, applying complex, discrete-event, models to a combination of pharmacokinetic data and prior physiological model parameters is a sparsely explored area. This example shows that although challenging, this is feasible.
References:
[1] Hénin, E et al. Tablet position in gastrointestinal tract derived from drug release measurements and plasma concentrations. PAGE 18-Abstr 1600 [www.page-meeting.org/?abstract=1600], 2009
[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, 2009. 86(1): p. 77-83
[3] Standing, JF et al. Population pharmacokinetics of oral diclofenac for acute pain in children. Br J Clin Pharmacol, 2008. 66(6): p846-53
[4] Korpela,R et al. Pharmacokinetics of intravenous diclofenac sodium in children. Eur J clin Pharmacol, 1990. 38: p. 293-5
[5] Willis,JV et al. The Pharmacokinetics of Diclofenac Sodium following intravenous and oral administration. Eur J Clin Pharmacol, 1979. 16: p. 405-10
Reference: PAGE 19 (2010) Abstr 1752 [www.page-meeting.org/?abstract=1752]
Poster: Other topics - Applications