Andrés Olivares-Morales (1), Leon Aarons (1), Amin Rostami-Hodjegan (1,2)
(1) Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK. (2) Simcyp Limited, Blades Enterprise Centre, Sheffield, UK
Objectives: Most of the current PBPK absorption models represent the different regions of the human GI tract as a series of transit compartments, where the small intestine (SI) is typically described by seven compartments [1]. The aim of this work was to develop and validate a reduced, yet mechanistic, PBPK absorption model that can be used for the prediction of drug absorption and first pass intestinal metabolism in the different regions of the GI tract.
Methods: The model was implemented in Matlab® 2014a as a system of 18 ODEs. The GI tract was described by five compartments (stomach, duodenum, jejunum, ileum and colon), where a non-linear transfer function was implemented and optimised to describe the small intestinal transit time (SITT). The drug was modelled either in the solid or dissolved state. Dissolution was predicted using different derivations of the Nernst-Brunner equation [2]. Regional GI absorption was allowed only for dissolved drug and it was assumed dependent on drug’s effective permeability (Peff). Regional variations in Peff were implemented in the model [3]. All the drug-specific and system-related parameters were taken from the literature. The model was used to predict the fraction absorbed (fabs) for 10 different drugs [4, 5]. In addition, the PK of the oxybutynin (OXY), a CYP3A-subtrate, was predicted when administered as immediate release (IR) and modified release (MR) [6, 7]. For the PK predictions, OXY’s disposition parameters were derived by fitting a three compartment model to intravenous (iv) data[7], while allowing the model to predict OXY’s absorption and first pass metabolism.
Results: The predicted fabs for the 10 investigated drugs was in good agreement with the observed data [4, 5]; the average absolute fold error was 1.2, whereas the concordance correlation coefficient was 0.94. A similar agreement was observed for OXY’s PK predictions, where the predicted PK parameters, AUC, Cmax, CLpo, were 16 ng/ml/h, 6.6 ng/mL and 314 L/h, respectively for the IR formulation, while for the MR formulation, the parameters were 95 ng/ml/h, 4 ng/mL and 158 L/h, respectively [6, 7].
Conclusions: The new model allowed the description of the SITT with a reduced number of SI compartments. The model also proved useful for the fabs predictions. The segmented structure of the model adequately captured the regional differences in absorption and first pass metabolism observed when OXY is administered as IR and MR [6,8].
References:
[1] Yu LX, Crison JR, Amidon GL. Compartmental transit and dispersion model analysis of small intestinal transit flow in humans. Int J Pharm 1996; 140: 111-18.
[2] Dokoumetzidis A, Macheras P. A century of dissolution research: From Noyes and Whitney to the Biopharmaceutics Classification System. Int J Pharm 2006; 321: 1-11.
[3] Olivares-Morales A. Aarons L., Rostami-Hodjegan A. Development and Application of Regional Intestinal Permeability Surface Area Scaling Factors for the Prediction of Oral Drug Absorption in the Distal GI Tract. Presented at AAPS Annual Meeting and Exposition 2014; Poster M1022 [http://abstracts.aaps.org/Verify/AAPS2014/PosterSubmissions/M1022.pdf]
[4] Yu LX, Amidon GL. A compartmental absorption and transit model for estimating oral drug absorption. Int J Pharm 1999; 186: 119-25.
[5] Lennernas H. Human in vivo regional intestinal permeability: importance for pharmaceutical drug development. Mol Pharm 2014; 11: 12-23.
[6] Gupta SK, Sathyan G. Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol 1999; 39: 289-96.
[7] Douchamps J, Derenne F, Stockis A, Gangji D, Juvent M, Herchuelz A. The pharmacokinetics of oxybutynin in man. Eur J Clin Pharmacol 1988; 35: 515-20.
[8] Olivares-Morales A, Kamiyama Y, Darwich AS, Aarons L, Rostami-Hodjegan A. Analysis of the impact of controlled release formulations on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model. Eur J Pharm Sci 2015; 67: 32-44.
Reference: PAGE 24 (2015) Abstr 3449 [www.page-meeting.org/?abstract=3449]
Poster: Drug/Disease modeling - Absorption & PBPK