Prediction of Modified Release Pharmacokinetics and Pharmacodynamics from In Vitro, Immediate Release, and Intravenous Data

Abstract. Regional intestinal effective permeability (P eff ) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P eff values. These new intestinal P eff values or Bintrinsic^P eff (P eff,int ) were subsequently employed for the prediction of the ileal absorption clearance (CL abs,ileum ) for a set of structurally diverse compounds. Additionally, the method was combined with a semimechanistic absorption PBPK model for the prediction of the fraction absorbed (f abs ). The results showed that P eff,int can successfully be employed for the prediction of the ileal CL abs and the f abs . P eff,int also showed to be a robust predictor of the f abs when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f abs observed for lowly permeable compounds when using the historical P eff values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.KEY WORDS: intestinal permeability; oral drug absorption; physiologically based pharmacokinetic modelling.

Section: Discussionmentioning

confidence: 99%

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Olivares‐Morales

Lennernäs

Aarons

et al. 2015

“…However there are relatively few reports specifically discussing the application of such models to MR products. Lukakova et al (14) described the use of absorption models developed in GastroPlus to accurately predict the observed pharmacokinetics of MR formulations of metoprolol, a BCS I compound and of Adinazolam. In the latter case, the model was based on fit of the in vivo release rates to the pharmacokinetic data since in vitro release data were not available.…”

Section: Discussionmentioning

confidence: 99%

“…Given the ability of oral absorption/PBPK models to project plasma concentration profiles based on in vitro data, they can also be used as an alternative method to establish an IVIVC (14). The traditional deconvolution/convolution method is more suitable for compounds with linear pharmacokinetics that are well-absorbed throughout the GI tract.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Deconvolution-Based and Absorption Modeling IVIVC for Extended Release Formulations of a BCS III Drug Development Candidate

Kesisoglou

Xia

Agrawal³

2015

Abstract. In vitro-in vivo correlations (IVIVC) are predictive mathematical models describing the relationship between dissolution and plasma concentration for a given drug compound. The traditional deconvolution/convolution-based approach is the most common methodology to establish a level A IVIVC that provides point to point relationship between the in vitro dissolution and the in vivo input rate. The increasing application of absorption physiologically based pharmacokinetic model (PBPK) has provided an alternative IVIVC approach. The current work established and compared two IVIVC models, via the traditional deconvolution/convolution method and via absorption PBPK modeling, for two types of modified release (MR) formulations (matrix and multi-particulate tablets) of MK-0941, a BCS III drug development candidate. Three batches with distinct release rates were studied for each formulation technology. A two-stage linear regression model was used for the deconvolution/convolution approach while optimization of the absorption scaling factors (a model parameter that relates permeability and input rate) in Gastroplus TM Advanced Compartmental Absorption and Transit model was used for the absorption PBPK approach. For both types of IVIVC models established, and for either the matrix or the multiparticulate formulations, the average absolute prediction errors for AUC and C max were below 10% and 15%, respectively. Both the traditional deconvolution/convolution-based and the absorption/PBPK-based level A IVIVC model adequately described the compound pharmacokinetics to guide future formulation development. This case study highlights the potential utility of absorption PBPK model to complement the traditional IVIVC approaches for MR products.

“…The two model compounds used in this example are metoprolol, a BCS 1 compound and ranitidine, a BCS 3 compound. The input parameters for the in silico model were taken from the literature and the both models were shown to predict the immediate release plasma concentration vs. time data (17,(23)(24)(25).…”

Section: Case Study 4-sensitivity Of Modified-release Formulation Tomentioning

confidence: 99%

“…The examples illustrate the pharmaceutics-based risk associated with the API and offer insights into the anticipated outcome from clinical studies. Other major applications in late-phase pharmaceutical product development include the assessment of modified release formulations (17) and making arguments for potential biowaivers of Biopharmaceutics Classification System (BCS) I or III compounds (18)(19)(20)(21) There are several additional areas that computational dissolution/absorption modeling can influence dosage form design and bioperformance. In this article, we discuss five case studies spanning the spectrum of formulation development activities from first-in-human formulation to life cycle management of mature products.…”

Section: Introductionmentioning

confidence: 99%

The Use of Modeling Tools to Drive Efficient Oral Product Design

Mathias

Crison

2012

Abstract. Modeling and simulation of drug dissolution and oral absorption has been increasingly used over the last decade to understand drug behavior in vivo based on the physicochemical properties of Active Pharmaceutical Ingredients (API) and dosage forms. As in silico and in vitro tools become more sophisticated and our knowledge of physiological processes has grown, model simulations can provide a valuable confluence, tying-in in vitro data with in vivo data while offering mechanistic insights into clinical performance. To a formulation scientist, this unveils not just the parameters that are predicted to significantly impact dissolution/absorption, but helps probe explanations around drug product performance and address specific in vivo mechanisms. In formulation, development, in silico dissolutionabsorption modeling can be effectively used to guide: API selection (form comparison and particle size properties), influence clinical study design, assess dosage form performance, guide strategy for dosage form design, and breakdown clinically relevant conditions on dosage form performance (pH effect for patients on pH-elevating treatments, and food effect). This minireview describes examples of these applications in guiding product development including those with strategies to mitigate observed clinical exposure liability or mechanistically probe product in vivo performance attributes.