Role of Physiological Intestinal Water in Oral Absorption

Abstract. Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling-(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

Section: Software Usedsupporting

confidence: 52%

Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm

Kesisoglou

Mitra

2015

“…BCS class 2 and 4 drugs. For those drugs, accounting for the GI physiological factors affecting the solubility, dissolution and precipitation along the GI tract is absolutely necessary, especially when it comes to the prediction and understanding of their regional intestinal absorption (4,25,(83)(84)(85). However, for our simulations, that assumption seemed reasonable as the majority of the drugs listed in Table II can be classified as highly soluble (BCS classes 1 and 3), with the exception of furosemide, which is poorly soluble weak acid (pKa=3.9), yet its solubility is expected to be high at the intestinal pH range (6-7.4) (85,86).…”

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

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.

“…8, 9a, 9b, 12a, and 12b for three drug constructs in a patient described by average physiological parameters. The value for small intestinal fluid volume (V l ) is 70 mL and the transit time (T l r) is 180 min, which represent median values from the literature (22,37,(44)(45)(46). The plateau concentration (C g p) was set to 10 μg/mL to reflect the low solubility values for many BCS II compounds, particularly those for which dissolution enhancement strategies, such as amorphization, are sought.…”

Section: Methodsmentioning

confidence: 99%

“…Using USP Apparatus (type 1 or 2), the volume ranges from 250 mL to 1 L (32), while the volume of the small intestinal fluid has been reported to be only 45 to 320 mL (37). The lower in vivo volume can result in a significantly lower amount of drug in solution in vivo (22). This is particularly important for amorphous formulations where the degree of supersaturation and excess remaining solid can influence the time course of precipitation (3).…”

Section: Relationship Between In Vitro Drug Concentration Profile Andmentioning

confidence: 99%

“…Current models range from simple equations to complex computer simulations. For instance, a simple model may use as few as four parameters to estimate drug absorption (e.g., the maximum absorbable dose (MAD) model considers only the absorption rate constant and solubility) (18,19), whereas computer models (e.g., GastroPlus™, Stella®, Intellipharm®, and Simcyp®) may utilize over 20 parameters (7,17,(19)(20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Mathematical Models to Explore Potential Effects of Supersaturation and Precipitation on Oral Bioavailability of Poorly Soluble Drugs

Kleppe

Forney-Stevens

Haskell

et al. 2015

Abstract. Poorly soluble drugs are increasingly formulated into supersaturating drug delivery systems which may precipitate during oral delivery. The link between in vitro drug concentration profiles and oral bioavailability is under intense investigation. The objective of the present work was to develop closedform analytical solutions that relate in vitro concentration profiles to the amount of drug absorbed using several alternate assumptions and only six parameters. Three parameters define the key features of the in vitro drug concentration-time profile. An additional three parameters focus on physiological parameters. Absorption models were developed based on alternate assumptions; the drug concentration in the intestinal fluid: (1) peaks at the same time and concentration as in vitro, (2) peaks at the same time as in vitro, or (3) reaches the same peak concentration as in vitro. The three assumptions provide very different calculated values of bioavailability. Using Case 2 assumptions, bioavailability enhancement was found to be less than proportional to in silico examples of dissolution enhancement. Case 3 assumptions lead to bioavailability enhancements that are more than proportional to dissolution enhancements. Using Case 1 predicts drug absorption amounts that fall in between Case 2 and 3. The equations developed based on the alternate assumptions can be used to quickly evaluate the potential improvement in bioavailability due to intentional alteration of the in vitro drug concentration vs. time curve by reformulation. These equations may be useful in making decisions as to whether reformulation is expected to provide sufficient bioavailability enhancement to justify the effort.