The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and ...efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo meeting in 2015 was dedicated to the presentation of the most recent progress in the development of the regulatory use of PBPK in silico modeling, in vivo predictive dissolution (IPD) tests, and their application to biowaivers. There are still several areas for improvement of in vitro dissolution testing by means of generating results relevant for the intraluminal conditions in the GI tract. The major opportunity is probably in combining IPD testing and physiologically based in silico models where the in vitro data provide input to the absorption predictions. The OrBiTo project and other current research projects include definition of test media representative for the more distal parts of the GI tract, models capturing supersaturation and precipitation phenomena, and influence of motility waves on shear and other forces of hydrodynamic origin, addressing the interindividual variability in composition and characteristics of GI fluids, food effects, definition of biorelevant buffer systems, and intestinal water volumes. In conclusion, there is currently a mismatch between the extensive industrial usage of modern in vivo predictive tools and very limited inclusion of such data in regulatory files. However, there is a great interest among all stakeholders to introduce recent progresses in prediction of in vivo GI drug absorption into regulatory context.
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OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one ...regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
Human jejunal permeability (Peff) is determined in the intestinal region with the highest expression of
carrier proteins and largest surface area. Intestinal Peff are often based on multiple parallel ...transport
processes. Site-specific jejunal Peff cannot reflect the permeability along the intestinal tract, but they are
useful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunal
Peff > 1.5 x 10–4 cm s–1 will be completely absorbed no matter which transport mechanism(s) are
utilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinal
absorption (i.e. >85%) mediated by passive transcellular diffusion. The determined jejunal Peff for
drugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) will
accurately predict the fraction of the dose absorbed as a consequence of the regional expression. The
data also show that: (1) the human intestinal epithelium has a large resistance towards large and
hydrophilic compounds; and (2) the paracellular route has a low contribution for compounds larger
than approximately molecular weight 200. There is a need for more exploratory in vivo studies to
clarify drug absorption and first-pass extraction along the intestine. One is encouraged to develop
in vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This would
stimulate the development of more relevant and complex in vitro absorption models and form the basis
for an accurate physiologically based pharmacokinetic modelling of oral drug absorption.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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Pharmaceutical excipients in drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may ...increase drug absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the intestinal drug absorption, it is defined as an absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase drug absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo intestinal absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the intestinal absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosal recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect intestinal drug absorption.
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Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients, or absorption-modifying excipients (AMEs) if they act by ...altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations.
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The small intestine mucosal barrier is physiologically regulated by the luminal conditions, where intestinal factors, such as diet and luminal tonicity, can affect mucosal ...permeability. The intestinal barrier may also be affected by absorption-modifying excipients (AME) in oral drug delivery systems. Currently, there is a gap in the understanding of how AMEs interact with the physiological regulation of intestinal electrolyte transport and fluid flux, and epithelial permeability. Therefore, the objective of this single-pass perfusion study in rat was to investigate the effect of three AMEs on the intestinal mucosal permeability at different luminal tonicities (100, 170, and 290 mOsm). The effect was also evaluated following luminal administration of a nicotinic receptor antagonist, mecamylamine, and after intravenous administration of a COX-2 inhibitor, parecoxib, both of which affect the enteric neural activity involved in physiological regulation of intestinal functions. The effect was evaluated by changes in intestinal lumen-to-blood transport of six model compounds, and blood-to-lumen clearance of 51Cr-EDTA (a mucosal barrier marker). Luminal hypotonicity alone increased the intestinal epithelial transport of 51Cr-EDTA. This effect was potentiated by two AMEs (SDS and caprate) and by parecoxib, while it was reduced by mecamylamine. Consequently, the impact of enteric neural activity and luminal conditions may affect nonclinical determinations of intestinal permeability. In vivo predictions based on animal intestinal perfusion models can be improved by considering these effects. The in vivo relevance can be increased by treating rats with a COX-2 inhibitor prior to surgery. This decreases the risk of surgery-induced ileus, which may affect the physiological regulation of mucosal permeability.
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Accurate in vivo predictions of intestinal absorption of low solubility drugs require knowing their solubility in physiologically relevant dissolution media. Aspirated human ...intestinal fluids (HIF) are the gold standard, followed by simulated intestinal HIF in the fasted and fed state (FaSSIF/FeSSIF). However, current HIF characterization data vary, and there is also some controversy regarding the accuracy of FaSSIF and FeSSIF for predicting drug solubility in HIF. This study aimed at characterizing fasted and fed state duodenal HIF from 16 human volunteers with respect to pH, buffer capacity, osmolarity, surface tension, as well as protein, phospholipid, and bile salt content. The fasted and fed state HIF samples were further used to investigate the equilibrium solubility of 17 representative low-solubility small-molecule drugs, six of which were confidential industry compounds and 11 were known and characterized regarding chemical diversity. These solubility values were then compared to reported solubility values in fasted and fed state HIF, FaSSIF and FeSSIF, as well as with their human bioavailability for both states. The HIF compositions corresponded well to previously reported values and current FaSSIF and FeSSIF compositions. The drug solubility values in HIF (both fasted and fed states) were also well in line with reported solubility data for HIF, as well as simulated FaSSIF and FeSSIF. This indicates that the in vivo conditions in the proximal small intestine are well represented by simulated intestinal fluids in both composition and drug equilibrium solubility. However, increased drug solubility in the fed vs. fasted states in HIF did not correlate with the human bioavailability changes of the same drugs following oral administration in either state.
Context:
Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release ...tablet with a more physiological exposure-time cortisol profile.
Objective:
The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets.
Design and Setting:
We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers.
Patients:
The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM).
Intervention:
The same daily dose of hydrocortisone was administered as OD dual-release or TID.
Main Outcome Measure:
We evaluated cortisol pharmacokinetics.
Results:
Compared with conventional TID, OD provided a sustained serum cortisol profile 0–4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = −0.7 kg, P = 0.005), systolic blood pressure (difference = −5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: −2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = −0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004).
Conclusion:
The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.
This study further evaluated the in vivo single-pass perfusion technique (LOC-I-GUT) in three different ways. First, the intestinal radius of the human small intestinal segment was measured on plain ...X-ray films; second, evaluation was performed by applying multislice computed tomography investigations; and third, furosemide was used as model drug in a transport study. In total 17 (6 + 4 +7) intubation/perfusion studies were performed in healthy volunteers. Mixobar was used as a positive radiographic contrast agent in the first six volunteers when plain film examination was made, followed by four studies using multislice computed tomography. Mantel area calculations of the perfused segment after X-ray investigations using barium as contrast were determined to be 101.0 ± 2.9 cm2. Maximal dilatation of the closed segment with room air as contrast and using MSCT revealed a mantel area of 121.30 ± 7.0 cm2 (P < 0.01). Thus, the mantle area increased a further 20% when the bowel was fully distended, reflecting different physiologic distention patterns for air and fluid. A jejunal single-pass perfusion study was performed in a further seven volunteers. In each experiment furosemide was perfused during 200 min, and in the treatment period (100−200 min), fexofenadine was added to the perfusion solution. The mean (±SD) P eff for furosemide was 0.17 ± 0.07 and 0.12 ± 0.09 × 10−4 cm/s in the control and treatment period, respectively. This study showed that the calculation of human in vivo permeability is based on physiological values, which are important for the wide application of these in vivo permeability data in physiologically based pharmacokinetic modeling.
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Particle size reduction is a traditional approach to increase the intestinal absorption of active pharmaceutical ingredients with poor intestinal solubility, by increasing the ...particle dissolution rate. However, an increase in the dissolution rate cannot always fully explain the effects of nanoformulations, and a method of assessing the potential benefits of a nanoformulation in vivo would hence be of great value in drug development. A novel mathematical model of a nanoformulation, including interlinked descriptions of the hydrodynamics, particle dissolution and diffusion of particles and colloidal structures (CS), was developed to predict the combined in vivo effects of these mechanisms on drug absorption. The model successfully described previously reported in vivo observations of nanoformulated aprepitant in rats, at various drug concentrations and in the presence or absence of CS. The increase in absorption rate was explained as a direct consequence of the increased drug concentration at the membrane, caused by the contributing effects of the diffusion of both nanoparticles and CS into which the drug had partitioned. Further simulations supported the conclusion that the model can be applied during drug development to provide a priori assessments of the potential benefits of nanoformulations.
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