Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption.
OBJECTIVE
Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated.


METHODS
Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics.


RESULTS
The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration-time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure.


CONCLUSIONS
The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.
Willmann
Stefan
S
Bayer Technology Services GmbH, Leverkusen, Germany. stefan.willmann@bayertechnology.com
Edginton
Andrea N
AN
Kleine-Besten
Marcus
M
Jantratid
Ekarat
E
Thelen
Kirstin
K
Dressman
Jennifer B
JB
D000284:Administration, Oral; D019540:Area Under Curve; D001682:Biological Availability; D002927:Cimetidine / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D003692:Delayed-Action Preparations; D005746:Gastric Emptying; D005772:Gastrointestinal Transit; D006635:Histamine H2 Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D013607:Tablets; D014018:Tissue Distribution
D003692:Delayed-Action Preparations; D006635:Histamine H2 Antagonists; D013607:Tablets; D002927:Cimetidine