In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 μmol/mL/ΔpH in fasted state (range: 0.26 and 6.32 μmol/mL/ΔpH) and 2.66 μmol/mL/ΔpH in fed state (range: 0.78 and 5.98 μmol/mL/ΔpH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions.

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The application of in silico modeling to predict the in vivo outcome of an oral drug product is gaining a lot of interest. Fully relying on these models as a surrogate tool requires continuous optimization and validation. To do so, intraluminal and systemic data are desirable to judge the predicted outcomes. The aim of this study was to predict the systemic concentrations of ibuprofen after oral administration of an 800 mg immediate-release (IR) tablet to healthy subjects in fasted-state conditions. A mechanistic oral absorption model coupled with a two-compartmental pharmacokinetic (PK) model was built in Phoenix WinNonlinWinNonlin® software and in the GastroPlus™ simulator. It should be noted that all simulations were performed in an ideal framework as we were in possession of a plethora of in vivo data (e.g., motility, pH, luminal and systemic concentrations) in order to evaluate and optimize these models. All this work refers to the fact that important, yet crucial, gastrointestinal (GI) variables should be integrated into biopredictive dissolution testing (low buffer capacity media, considering phosphate versus bicarbonate buffer, hydrodynamics) to account for a valuable input for physiologically-based pharmacokinetic (PBPK) platform programs. While simulations can be performed and mechanistic insights can be gained from such simulations from current software, we need to move from correlations to predictions (IVIVC → IVIVP) and, moreover, we need to further determine the dynamics of the GI variables controlling the dosage form transit, disintegration, dissolution, absorption and metabolism along the human GI tract. Establishing the link between biopredictive in vitro dissolution testing and mechanistic oral absorption modeling (i.e., physiologically-based biopharmaceutics modeling (PBBM)) creates an opportunity to potentially request biowaivers in the near future for orally administered drug products, regardless of its classification according to the Biopharmaceutics Classification System (BCS).

Aims To evaluate the relative bioavailability of oral amoxicillin (AMX) tablets in comparison to AMX suspension in Roux‐en‐Y gastric bypass bariatric subjects. Methods A randomized, double‐blind, cross‐over study was performed on the bioavailability of oral AMX tablets and suspension in Roux‐en‐Y gastric bypass subjects operated at least 3 months previously . Doses of 875 mg of the AMX tablet or 800 mg of the AMX suspension were given to all the subjects, allowing a washout of 7 days between the periods. Blood samples were collected at 0, 0.25, 0.5, 1, 1.5, 2, 4, 6 and 8 hours after drug administration and the AMX levels were quantified by liquid chromatography coupled with triple quadrupole tandem mass spectrometry. The pharmacokinetic parameters were calculated by noncompartmental analysis, normalized to an 875 mg dose and the bioavailability of the AMX from the tablets was compared to that from the suspension formulation. Results Twenty subjects aged 42.65 ± 7.21 years and with a body mass index of 29.88 ± 4.36 kg/m2 were enrolled in the study. The maximum AMX plasma concentration of the tablets and the suspension (normalized to 875 mg) were 7.42 ± 2.99 mg/L and 8.73 ± 3.26 mg/L (90% confidence interval of 70.71–99.11), and the total area under the curve from time zero to infinity were 23.10 ± 7.41 mg.h/L and 27.59 ± 8.32 mg.h/L (90% confidence interval of 71.25–97.32), respectively. Conclusion The tablets presented a lower bioavailability than the suspension formulation and the total absorbed amount of AMX in these subjects was lower in comparison to the standard AMX absorption rates in nonbariatric subjects, regardless of the formulation.

Over the past decade, formulation predictive dissolution (fPD) testing has gained increasing attention. Another mindset is pushed forward where scientists in our field are more confident to explore the in vivo behavior of an oral drug product by performing predictive in vitro dissolution studies. Similarly, there is an increasing interest in the application of modern computational fluid dynamics (CFD) frameworks and high-performance computing platforms to study the local processes underlying absorption within the gastrointestinal (GI) tract. In that way, CFD and computing platforms both can inform future PBPK-based in silico frameworks and determine the GI-motility-driven hydrodynamic impacts that should be incorporated into in vitro dissolution methods for in vivo relevance. Current compendial dissolution methods are not always reliable to predict the in vivo behavior, especially not for biopharmaceutics classification system (BCS) class 2/4 compounds suffering from a low aqueous solubility. Developing a predictive dissolution test will be more reliable, cost-effective and less time-consuming as long as the predictive power of the test is sufficiently strong. There is a need to develop a biorelevant, predictive dissolution method that can be applied by pharmaceutical drug companies to facilitate marketing access for generic and novel drug products. In 2014, Prof. Gordon L. Amidon and his team initiated a far-ranging research program designed to integrate (1) in vivo studies in humans in order to further improve the understanding of the intraluminal processing of oral dosage forms and dissolved drug along the gastrointestinal (GI) tract, (2) advancement of in vitro methodologies that incorporates higher levels of in vivo relevance and (3) computational experiments to study the local processes underlying dissolution, transport and absorption within the intestines performed with a new unique CFD based framework. Of particular importance is revealing the physiological variables determining the variability in in vivo dissolution and GI absorption from person to person in order to address (potential) in vivo BE failures. This paper provides an introduction to this multidisciplinary project, informs the reader about current achievements and outlines future directions.

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