Prediction of negative food effect induced by bile micelle binding on oral absorption of hydrophilic cationic drugs

Lost in modelling and simulation?

“…For example, in a physiologically-based solubility model (Figure 2B), the pH and the bile micelle concentration (C bm ) are used as physiological parameters, and the intrinsic solubility (S 0 ), pK a , and bile micelle partition coefficients (K bm ) (for each unionized and ionized drug molecules) are used as drug parameters [35,39,40]. Physiologically-based dissolution [41][42][43][44][45][46][47][48] and permeation [49][50][51][52][53][54][55] where X undissolv and X dissolv are the amounts of a drug undissolved and dissolved in the gastrointestinal fluid, respectively. D eff is the effective diffusion coefficient, Dose is the dose strength, ρ is the true density of the drug substance, and r p is the particle radius (r p < 30 μm).…”

“…It is well known that the effective intestinal membrane permeability (P eff ) is markedly affected by bile micelle binding [51,[91][92][93][94], the unstirred water layer (UWL) [74,[95][96][97][98], and the anatomical features (villi and fold structures) [99] (section 2.1) (cf. the P eff value includes the free fraction effects by definition in most cases of commercial software).…”

“…Finally, and most importantly, this equation is an empirical correlation so that it should not be referred to as "physiologically-based". A mechanistic physiologically-based permeation model that considers these factors is available in the literature (section 2.1) [49][50][51][52][53][54][55] and in some commercial software products.…”

“…A simple OA PBPK model has shown good prediction performance for the fraction of a dose absorbed (F a ) [5,50,79,83,134] and plasma concentration (C p ) -time profiles [135][136][137][138][139][140][141][142][143]. For relative bioavailability (F rel ) prediction, a simple OA-PBPK model is also available for the food effect (via bile micelles) and gastric acid effect predictions [51,79,100]. By multiplying AUC in the fasted state (or low gastric pH) with F rel (i.e., AUC ratio), AUC in the fed state (or high gastric pH) can be estimated.…”

“…It was implicitly assumed that the k perm values in the fasted and fed states are the same. However, it is well known that bile micelle binding reduces the free fraction, the effective diffusion coefficient, and consequently P eff and k perm (section 2.7) [51,91,92,94,147,148]. The predictive power of a model cannot be validated by the same data used for parameter backcalculation (section 3.11).…”