Benjamin Guiastrennec (1), Erik Söderlind (2), Sara Richardson (2), Martin Bergstrand (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden
Objectives: To predict in vitro and in vivo erosion rate for several of hydroxypropyl methylcellulose (HPMC) and dicalcium phosphate (DCP) based gel matrix tablets, under fasting and fed conditions and to integrate findings in an interactive simulation tool.
Methods: Data were available from a previously published study where in vitro erosion profiles of 4 tablet formulation with various amount of HPMC and DCP were assessed under a range of pH and mechanical stress (rpm) [1]. A study was also conducted in healthy volunteers (n=5) to simultaneously measure the in vivo erosion rate and the gastrointestinal (GI) location of the tablets under fasting and fed conditions. A previously published tablet volume model and a Michaelis-Menten like model were evaluated on the in vitro data [2]. Stepwise covariate modeling (SCM) was used to investigate the effect of tablet formulation and experimental conditions (pH, rpm) on the model parameters. The in vitro model and its final estimates were used to predict in vivo erosion profiles. The pH in the different GI locations was fixed to literature values while the mechanical stress was estimated for each GI segment [3,4]. R and the package Shiny were used to create the interactive simulation tool [5].
Results: The Michaelis-Menten like model was selected over the tablet volume model. The final estimates were 22.79 mg/h for VMAX and 29.42 mg for KM. The SCM identified significant (α = 5 %) effect of pH and DCP on KM and pH, DCP, HPMC and rpm on VMAX. The in vivo mechanical stress was estimated to 26.3 rpm in fasting stomach, 90.8 rpm in fed stomach, 44.6 rpm in small intestine and 25.1 rpm in colon. In vivo predictions were in good agreement with the observed erosion rates, except the formulation with the lowest amount of HPMC under fasting condition, which was overpredicted.
Conclusions: The in vitro erosion model successfully predicted the erosion in vivo under fed and fasting conditions. Model misspecification for one of the formulation was suspected, as HPMC concentrations were too low to form a proper gel matrix. Significantly lower estimates for in vivo mechanical stress in comparison with previous publication may indicate that some factors in the in vitro-in vivo translation are yet to be characterized [2]. The integration of the model in a simulation tool will ease future in vitro-in vivo translation.
Acknowledgements: This work was supported by AstraZeneca. References:
[1] Kumar Jain A. et al. The influence of hydroxypropyl methylcellulose (HPMC) molecular weight, concentration and effect of food on in vivo erosion behavior of HPMC matrix tablets. Journal of Controlled Release, 187, 50–58. (2014)
[2] Bergstrand M. et al. A Semi-mechanistic Modeling Strategy to Link In Vitro and In Vivo Drug Release for Modified Release Formulations. Pharm Res, 29, 695–706. (2012)
[3] Evans DF. et al. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut, 29(8), 1035–1041. (1988)
[4] Simonian HP et al. Regional postprandial differences in pH within the stomach and gastro-esophageal junction. Dig Dis Sci, 50(12), 2276–2285. (2005)
[5] RStudio Inc. Shiny: web application framework for R. R package version 0.8.0. [Available at: http://CRAN.R-project.org/package=shiny] (2013)
Reference: PAGE 24 () Abstr 3469 [www.page-meeting.org/?abstract=3469]
Poster: Drug/Disease modeling - Absorption & PBPK