title: In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim.
abstract: Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation. This study discloses an evaluation of the predictive performance of the mechanistic physiologically based absorption model GI-Sim. GI-Sim deploys a compartmental gastrointestinal absorption and transit model as well as algorithms describing permeability, dissolution rate, salt effects, partitioning into micelles, particle and micelle drifting in the aqueous boundary layer, particle growth and amorphous or crystalline precipitation. Twelve APIs with reported or expected absorption limitations in humans, due to permeability, dissolution and/or solubility, were investigated. Predictions of the intestinal absorption for different doses and formulations were performed based on physicochemical and biopharmaceutical properties, such as solubility in buffer and simulated intestinal fluid, molecular weight, pK(a), diffusivity and molecule density, measured or estimated human effective permeability and particle size distribution. The performance of GI-Sim was evaluated by comparing predicted plasma concentration-time profiles along with oral pharmacokinetic parameters originating from clinical studies in healthy individuals. The capability of GI-Sim to correctly predict impact of dose and particle size as well as the in vivo performance of nanoformulations was also investigated. The overall predictive performance of GI-Sim was good as >95% of the predicted pharmacokinetic parameters (C(max) and AUC) were within a 2-fold deviation from the clinical observations and the predicted plasma AUC was within one standard deviation of the observed mean plasma AUC in 74% of the simulations. GI-Sim was also able to correctly capture the trends in dose- and particle size dependent absorption for the study drugs with solubility and dissolution limited absorption, respectively. In addition, GI-Sim was also shown to be able to predict the increase in absorption and plasma exposure achieved with nanoformulations. Based on the results, the performance of GI-Sim was shown to be suitable for early risk assessment as well as to guide decision making in pharmaceutical formulation development.
authors.affiliation: Department of Pharmacy, Uppsala University, BOX 580, S-751 23 Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Sjögren
authors.forename: Jan
authors.initials: J
authors.lastname: Westergren
authors.forename: Iain
authors.initials: I
authors.lastname: Grant
authors.forename: Gunilla
authors.initials: G
authors.lastname: Hanisch
authors.forename: Lennart
authors.initials: L
authors.lastname: Lindfors
authors.forename: Hans
authors.initials: H
authors.lastname: Lennernäs
authors.forename: Bertil
authors.initials: B
authors.lastname: Abrahamsson
authors.forename: Christer
authors.initials: C
authors.lastname: Tannergren
mesh_terms: D018938:Caco-2 Cells; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations
keywords: AAF; ABL; ACAT; ADAM; API; AUC; Absorption modeling; BCS; BSA; Biopharmaceutics Classification System; Boltzmann’s constant; CAT; CYP3A4; Caco-2 apparent permeability; D; F; FaSSIF; Fraction absorbed; GI; In silico prediction; Intestinal permeability; L; M(w); P; P(ABL); P(app); P(eff); P(m); R; S; Solubility; V(M); active pharmaceutical ingredient; advanced compartmental absorption and transit; advanced dissolution absorption and metabolism; aqueous boundary layer; aqueous boundary layer thickness; area amplification factor; area under the plasma concentration time curve; bioavailability; bovine serum albumin; compartmental absorption and transit; cytochrome P450 3A4; diffusion coefficient in water; f(0); f(abs); f(stirring); fasted simulated small intestinal fluid; fraction absorbed; fraction of dissolved active pharmaceutical ingredient partitioned to micelles; fraction uncharged; gastrointestinal; human effective jejunal permeability; k; membrane permeability; molar density; molar volume; molar weight; molecule radius; particle radius; permeability; permeability in the aqueous boundary layer; q; r; solubility; stirring factor; transit time; viscosity of water; η; ρ; τ