Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans—Part 1: Fasted State Conditions

Bermejo, Marival; Paixão, Paulo; Hens, Bart; Tsume, Yasuhiro; Koenigsknecht, Mark J.; Baker, Jason; Hasler, William L.; Lionberger, Robert; Fan, Jianghong; Dickens, Joseph; Shedden, Kerby; Wysocki, Jeffrey; Löbenberg, Raimar; Lee, Allen; Frances, Ann; Amidon, Gregory E.; Yu, Alex; Salehi, Niloufar; Talattof, Arjang; Benninghoff, Gail; Sun, Duxin; Kuminek, Gislaine; Cavanagh, Katie L.; Rodrı́guez-Hornedo, Naı́r; Amidon, Gordon L.

doi:10.1021/acs.molpharmaceut.8b00515

Cited by 23 publications

(8 citation statements)

References 43 publications

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“…The hydrodynamics of the GI lumen are dynamic and dependent on the amount of fluid present and the contractile activity of the muscles surrounding the GI lumen. , It is hypothesized that the ABLs surrounding dissolving particles and the GI lumen within these water pockets are significant barriers to dissolution and absorption for certain poorly soluble APIs. Furthermore, it is expected that the hydrodynamics of these fluid pockets will vary locally and may yield a distribution of ABL thicknesses.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it is expected that the hydrodynamics of these fluid pockets will vary locally and may yield a distribution of ABL thicknesses. In a study evaluating the intersubject variability exposure of ibuprofen, a BCS Class II drug, Amidon and co-workers have identified the variability to be a result of motility differences across subjects. , It has been suggested that slower transit times due to lower contractile activity could lead to decreased agitations of the ABLs surrounding dissolving particles . Therefore, for poorly soluble drugs whose permeability is limited by the transport through the ABL, it is expected that the sensitivity to nanospeciation would be significant. , …”

Section: Discussionmentioning

confidence: 99%

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Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

et al. 2020

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Enabling formulations are an attractive approach to increase the dissolution rate, solubility, and oral bioavailability of poorly soluble compounds. With the growing prevalence of poorly soluble drug compounds in the pharmaceutical pipeline, supersaturating drug delivery systems (SDDS), a subset of enabling formulations, have grown in popularity due to their properties allowing for drug concentrations greater than the corresponding crystalline solubility. However, the extent of supersaturation generated as the enabling formulation traverses the gastrointestinal (GI) tract is dynamic and poorly understood. The dynamic nature of supersaturation is a result of several competing kinetic processes such as dissolution, solubilization by formulation and endogenous surfactants, crystallization, and absorption. Ultimately, the free drug concentration, which is equivalent to the drug's inherent thermodynamic activity amid these kinetic processes, defines the true driving force for drug absorption. However, in cases where solubilizing agents are present (i.e., surfactants and bile salts), drug molecules may associate with colloidal nanoscale species, complicating drug activity determination. These nanoscale species can drift into the aqueous boundary layer (ABL), increasing the local API activity at the membrane surface, resulting in increased bioavailability. Herein, a novel approach was developed to accurately measure thermodynamic drug activity in complex media containing drug distributed in nanoparticulate species. This approach captures the influence of the ABL on the observed flux and, ultimately, the predicted unbound drug concentration. The results demonstrate that this approach can help to (1) measure the true extent of local supersaturation in complex systems containing solubilizing excipients and (2) elucidate the mechanisms by which colloidal aggregates can modulate the drug activity in solution and potentially enhance the flux observed across a membrane. The utilization of these techniques may provide development scientists with a strategy to evaluate formulation sensitivity to nanospeciation and allow formulators to maximize the driving force for absorption in a complex environment, perhaps enabling the development of dissolution methods with greater discrimination and correlation to pre-clinical and clinical data sets.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

et al. 2020

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“…Immediate-release (IR) orally administered drug products need to be first dissolved in the gastrointestinal (GI) tract and then be absorbed through the small intestine’s epithelial cell membrane to reach systemic circulation. , According to the biopharmaceutics drug classification system (BCS), dissolution is the rate-limiting process for the oral delivery of BCS class II drugs with low solubility and high permeability . The in vivo dissolution rate of drug products is governed by drug properties such as p K a , intrinsic solubility, and particle size, in addition to the physiological parameters such as gastric emptying rate, hydrodynamic conditions generated due to the intestinal motility, buffer species, buffer capacity, ionic strength, bile salts, and pH .…”

Section: Introductionmentioning

confidence: 99%

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis

et al. 2021

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Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the GI tract’s physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. et al. Mol. Pharm. 2018 and Bermejo, et al. M. Mol. Pharm. 2018). The dissolution of an ionizable drug may benefit from manipulating in vivo variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (i.e., proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds’ dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties (e.g., solubility and pK a) and its interplay with the pH modifier pK a or pK as. As an example of this complex interaction, for basic drugs with high pK a and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as pK a, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to in vitro multi-compartment dissolution vessels and are validated by in vitro experiments in the gastrointestinal simulator. This model’s predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both in vitro and in vivo conditions.

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“…Taken together, all the systemic availability events of CellCept are controlled by GE ibuprofen. 39 In addition, it has been experimentally demonstrated that delayed GE was associated with a longer T max and lower C max , but the total exposure to MPA was not affected. 24 More GI dynamics get involved under fed conditions due to the significantly slower dissolution rate in the elevated pH range.…”

Section: ■ Discussionmentioning

confidence: 99%

In Vitro Predictive Dissolution Test Should Be Developed and Recommended as a Bioequivalence Standard for the Immediate-Release Solid Oral Dosage Forms of the Highly Variable Mycophenolate Mofetil

Wang

Chen

et al. 2022

Mol. Pharmaceutics

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The prodrug mycophenolate mofetil (MMF), which is presystemically hydrolyzed into the pharmacologically active compound mycophenolic acid (MPA), has been widely used for the prophylaxis of acute allograft rejection in solid organ transplantation. However, the huge variability in the plasma concentration level makes the development of MMF drug products difficult due to the great challenge of meeting the traditional bioequivalence (BE) limits. Numerous models have been developed in the past decade to explain the variability, with the emphasis on characterizing the enterohepatic circulation. While the variability arising from systemic appearance can also contribute to the remarkable MPA variability to a great extent, it has been ignored for long for this Biopharmaceutics Classification System class 2 drug. To improve the design of the BE study for this highly variable (HV) drug, the variability of MMF pharmacokinetic (PK) profiles focusing on the absorption process was explored in a population approach. A total of 81 Chinese adult liver transplant recipients were enrolled and had their plasma concentrations of MPA and its metabolites measured by HPLC during one visit or multiple visits in a long-term MMF regimen. The population models were developed using NONMEM, and the data and the results of the model were analyzed by R. Two population PK models of MMF focusing on the absorption process were developed based on the plasma concentrations of MPA and its major metabolite 7-O-MPA-β-glucuronide (MPAG). The MPA PK profiles were best characterized by a two-compartment disposition model with zero inter-individual variability (IIV) of elimination coefficient (K20), lag time, but considerable intra-individual variability (IAV) in the form of inter-occasion variability regarding systemic appearance coefficient, K20, and central volume of distribution, when just using MPA plasma concentrations as observations. The second model took into consideration the EHC by including MPAG profiles as well. The results from both models showcased that the IAV played a far more significant role than the IIV in accounting for the variability of the MMF systemic appearance. This is in line with what was found in the BE study: the within-subject variability (WSV) of BE measures largely exceeded the corresponding between-subject variability. The great WSV of MMF can be mechanistically explained by the interplay of dissolution and solubility with the gastrointestinal (GI) physiological dynamics, especially the gastric emptying (GE) in the fasting state regulated by migrating motor complex, and GE and pH variations in the fed state by the caloric content with irregular patterns of GI motility and secretion. The results implied that for the immediate-release solid oral dosage forms of MMF, running a regular in vitro dissolution test for the fasting state and developing a predictive in vitro dissolution test with sufficient simulation of the GE dynamics and proximal small intestinal pH fluctuations for the fed state would be excellent surrogates f...

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Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans—Part 1: Fasted State Conditions

Cited by 23 publications

References 43 publications

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis

In Vitro Predictive Dissolution Test Should Be Developed and Recommended as a Bioequivalence Standard for the Immediate-Release Solid Oral Dosage Forms of the Highly Variable Mycophenolate Mofetil

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