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Dynamic in vitro absorption systems and mechanistic absorption modeling via PBPK have both shown promise in predicting human oral absorption, although these efforts have been largely separate; this work aimed to integrate knowledge from these approaches to investigate the oral absorption of a RET inhibitor, pralsetinib, with BCS Class II properties. Tiny-TIM (TIM B.V., Weteringbrug​, The Netherlands) is a dynamic in vitro model with close simulation of the successive physiological conditions of the human stomach and small intestine. Tiny-TIM runs with pralsetinib were performed at doses of 200 mg and 400 mg under fasting conditions. Mechanistic modeling of absorption was performed in Simcyp V21 (Certara, Manchester, UK). Pralsetinib fasted bioaccessibility in the Tiny-TIM system was 63% at 200 mg and 53% at 400 mg; a 16% reduction at 400 mg was observed under elevated gastric pH. Maximum pralsetinib solubility from the small intestinal compartment in Tiny-TIM directly informed the supersaturation/precipitation model parameters. The PBPK model predicted a similar fraction absorbed at 200 mg and 400 mg, consistent with the dose proportional increases in observed pralsetinib exposure. Integrating dynamic in vitro systems with mechanistic absorption modeling provides a promising approach for understanding and predicting human absorption with challenging low solubility compounds. [ABSTRACT FROM AUTHOR]

A new regression model is presented which offers flexibility, freedom from subjective determinations of linear range, and very wide applicability to measurement systems of industrial importance. This "progressive decay" model starts as a deceptively simple ordinary differential equation. We show here that its solution faithfully describes real but seemingly unconnected data from a plate-based assay for quantitation of RNA with RiboGreen® and dissolution data for a triple fixed-dose combination solid oral dosage form. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are important transporters causing drug-drug interaction (DDI). Here, we investigated the involvement of P-gp and BCRP in the oral absorption of ensitrelvir in non-clinical studies and estimated the DDI risk mediated by P-gp and BCRP inhibition in humans. Although ensitrelvir is an in vitro P-gp and BCRP substrate, it demonstrated high bioavailability in rats and monkeys after oral administration. Plasma exposures of ensitrelvir following oral administration were comparable in wild type (WT) and Bcrp (-/-) mice. On the other hand, the area under the plasma concentration-time curve (AUC) ratio of ensitrelvir in the Mdr1a/1b (-/-) mice to the WT mice was 1.92, indicating that P-gp, but not BCRP, was involved in the oral absorption of ensitrelvir. Based on our previous retrospective analyses, such a low AUC ratio (<3) in the Mdr1a/1b (-/-) mice indicates a minimal impact of P-gp on the oral absorption in humans. In conclusion, our studies demonstrate that the involvement of both P-gp and BCRP in the oral absorption of ensitrelvir is minimal, and suggest that ensitrelvir has a low risk for DDIs mediated by P-gp and BCRP inhibition in humans. [Display omitted] [ABSTRACT FROM AUTHOR]

The addition of antioxidants to pharmaceutical products is a potential approach to inhibit nitrosamine formation, particularly in solid oral dosage forms like tablets and capsules. The objective was to assess the effect of ten antioxidants on the permeability of four Biopharmaceutics Classification System (BCS) Class III drugs. Bi-directional drug permeability studies in the absence and presence of antioxidants were performed in vitro across MDCK-II monolayers. No antioxidant increased drug permeability, while the positive control sodium lauryl sulfate always increased drug permeability. Results support that any of the ten antioxidants, up to at least 10 mg, can be added to a solid oral dosage form without modulating passive drug intestinal permeability. Additional considerations are also discussed. [ABSTRACT FROM AUTHOR]

Safety and efficacy are the most critical factors for the development of modern medications. For oral drugs, evaluating drug exposure under various conditions is one of the most important outcomes for clinical trials. These data will help to better understand the safety and efficacy of new drugs. Studies involving potential drug-drug interactions, proton pump inhibitors, and intake of food are often conducted to assess the above. Among the above, the influence of food on exposure to the drug is one of the key data sets for regulatory submission. Since food may have either a positive or negative effect on drug exposure, it is important to obtain an early assessment of the food effect. To better forecast and plan for clinical studies, substantial efforts have been made in the industry to develop modeling and in-vitro and in–vivo assays. Despite the efforts, predicting the effect of food on exposure without integrating the dynamic of the gastrointestinal tract in the assessment remains challenging. In this study, we evaluated the utilization of the dynamic Gastro-Intestinal Model (Tiny-TIM) for the food effect of over 20 drugs/formulations in development or on the market that covers all BCS classes. In general, the Tiny-TIM predicted food effects were in good agreement with the reported data in humans. This suggests that Tiny-TIM can successfully capture the impact of physicochemical properties on absorption under the influence of food. [ABSTRACT FROM AUTHOR]

Water-in-oil-in-water (w/o/w) double emulsions have shown excellent capability in augmenting the enteral bioavailability of BCS class III drugs, besides being effective controlled-release formulations. However, the problem of thermodynamic instability has restrained their industrial applicability. The self-double emulsifying drug delivery system (SDEDDS) is one of several approaches used to improve the stability of double emulsions. SDEDDS is a mixture of primary emulsion and secondary surfactant that can spontaneously emulsify into double emulsions in an external aqueous environment with mild agitation. Here, we prepared SDEDDS of gentamicin sulfate by response surface methodology. Selected optimized formulations (ODS1 and ODS2) were evaluated for zeta potential (Y1), optical clarity (Y2), release at 420 min (Y3), emulsion stability index (Y4) and self-emulsification time (Y5). For ODS1, Y1=−35.45 (±1.06)mV, Y2=53.19 (±0.35)%, Y3=75.79 (±0.60)%, Y4=93.97(±0.15)% and Y5=0.631 (±0.014)min, whereas for ODS2, Y1=−35.70 (±0.56)mV, Y2=48.09 (±0.64)%, Y3=76.61 (±0.99)%, Y4=93.00(±0.94)% and Y5=0.687(±0.02)min. Furthermore, ex-vivo studies on intestinal permeability revealed that SDEDDS improved membrane permeability compared to drug solution. Histopathology investigations revealed that SDEDDS promoted permeation without causing significant local membrane distortion. In addition, in - vivo studies revealed a 2.84 -fold increase in AUC 0-∞ of optimized SDEDD compared to pure drug oral solution. [ABSTRACT FROM AUTHOR]

A Biopharmaceutics Classification System (BCS)-based biowaiver monograph is presented for isavuconazonium sulfate. A BCS-based biowaiver is a regulatory option to substitute appropriate in vitro data for in vivo bioequivalence studies. Isavuconazonium sulfate is the prodrug of isavuconazole, a broad-spectrum azole antifungal indicated for invasive fungal infections. While the prodrug can be classified as a BCS Class III drug with high solubility but low permeability, the parent drug can be classified as a BCS Class II drug with low solubility but high permeability. Interestingly, the in vivo behavior of both is additive and leads isavuconazonium sulfate to act like a BCS class I drug substance after oral administration. In this work, experimental solubility and dissolution data were evaluated and compared with available literature data to investigate whether it is feasible to approve immediate release solid oral dosage forms containing isavuconazonium sulfate according to official guidance from the FDA, EMA and/or ICH. The risks associated with waiving a prodrug according to the BCS-based biowaiver guidelines are reviewed and discussed, noting that current regulations are quite restrictive on this point. Further, results show high solubility but instability of isavuconazonium sulfate in aqueous media. Although experiments on the dissolution of the capsule contents confirmed 'very rapid' dissolution of the active pharmaceutical ingredient (API) isavuconazonium sulfate, its release from the commercial marketed capsule formulation Cresemba is limited by the choice of capsule shell material, providing an additional impediment to approval of generic versions via the BCS-Biowaiver approach. [ABSTRACT FROM AUTHOR]

• This paper describes a Paxlovid PBPK Model that utilizes the ADAM module to better describe oral absorption of nirmatrelvir. • Rotamer conversion influences nirmatrelvir dissolution and absorption and was incorporated into the ADAM PBPK model. • PBPK model describes nirmatrelvir dissolution as a function of drug and drug product attributes, and physiological changes. • The Paxlovid ADAM PBPK model illustrates the importance of taking mechanistic approaches to model development. PAXLOVID™ is a combination medicine of nirmatrelvir tablets co-packaged with ritonavir tablets. Nirmatrelvir is a peptidomimetic inhibitor of SARS-CoV2 main protease (Mpro), developed for the treatment of COVID-19. Ritonavir is co-administered as a pharmacokinetics (PK) enhancer to inhibit CYP3A mediated metabolism increasing exposures of nirmatrelvir. In the solid form, nirmatrelvir exists in a stable single conformational state (ANTI form). However, nirmatrelvir exhibits atropisomerism in solution whereby upon dissolution the ANTI rotational isomer reversibly converts to another conformation state (SYN form). Nirmatrelvir rotamer conversion follows pseudo first order kinetics with a conversion half-life of approximately 15 min in aqueous solutions, which is on a similar time scale of diffusion mediated dissolution from the solid form. In vitro dissolution studies further indicated that rotamer conversion is one of the processes controlling nirmatrelvir dissolution. It was hypothesized that rotamer conversion kinetics would affect oral absorption of nirmatrelvir in vivo. Consequently, a physiologically based pharmacokinetic (PBPK) model for Paxlovid was developed in Simcyp™ using the advanced dissolution, absorption, and metabolism model (ADAM) by incorporating rotamer conversion kinetics to achieve a more mechanistic description of nirmatrelvir oral absorption. The results demonstrate that the established absorption model with rotamer kinetics adequately described observed clinical data from various nirmatrelvir doses, dosage forms, and dosing regimens. The predicted vs. observed AUC inf and C max ratios were within 2-fold. The model has been internally used to inform clinical studies and dose recommendations for pediatrics. [ABSTRACT FROM AUTHOR]

Here I detail the use of measures of permeability rate and solubility in predicting drug disposition characteristics through the utilization of the Biopharmaceutics Drug Disposition Classification System (BDDCS) and the Extended Clearance Classification System (ECCS) as well as the accuracy of the systems in predicting the major route of elimination and the extent of oral absorption of a new small molecule therapeutics. I compare the BDDCS and ECCS with the FDA Biopharmaceutics Classification System (BCS). I also detail the use of the BCS in predicting food effects and the BDDCS in predicting brain disposition of small molecule therapeutics and in validating DILI predictive metrics. This review provides an update of the current status of these classification systems and their uses in the drug development process. [ABSTRACT FROM AUTHOR]

The pharmacopoeial test method "Intrinsic Dissolution" (Ph.Eur. 2.9.29) is used to study the rate of dissolution for powders of active pharmaceutical ingredients normalized by the surface area. Therefore, powders are compacted into a special metal die holder, which is immersed into a dissolution vessel of the dissolution test apparatus (described in Ph.Eur. 2.9.3). However, in some cases, the test cannot be performed because the compacted powder would not stay in the die holder when in contact with the dissolution medium. In this study, we investigated the removable adhesive gum (RAG) as an alternative to the official die holder. Intrinsic dissolution tests were carried out to exemplify the use of the RAG for this purpose. As model substances, acyclovir and its co-crystal with glutaric acid were used. The RAG was validated for compatibility, release of extractables, unspecific adsorption and the ability to block drug release through the covered surfaces. The results showed that the RAG leaked no unwanted substances, showed no adsorption of acyclovir and blocked its release from covered surfaces. The intrinsic dissolution tests revealed, as expected, a constant release of drug with a small standard deviation between replicates. It was possible to distinguish the acyclovir release from the co-crystal and from the pure drug compound. In conclusion, the findings of this study suggest to consider removable adhesive gum as an easy-to-use and inexpensive alternative to the compendial die holder in intrinsic dissolution tests. [Display omitted] [ABSTRACT FROM AUTHOR]

For supersaturating formulations of BCS-II compounds, which by definition have high intestinal permeability, a closed USP apparatus does not provide the necessary absorptive conditions during dissolution. To address this, an artificial gut simulator (AGS) has been constructed consisting of a 2.5 mL donor compartment in which a hollow fiber-based absorption module is suspended. Drug from donor diffuses across the hollow fiber membrane to be absorbed by the continuously flowing intraluminal receiver fluid. The membrane surface area and intraluminal fluid flow rate are tuned to obtain the physiologically observed absorption rate constant for a weakly basic, poorly water-soluble model compound, ketoconazole (KTZ). Supersaturated solutions of KTZ were generated in the donor in pH 6.5 phosphate buffer by the pH-shift method in the absence (closed system, control) and presence (open system, biorelevant) of an optimally or suboptimally tuned absorption module. Drug concentrations in the donor and intraluminal fluids were determined by in-line UV spectroscopy. The presence of an absorptive sink reduced the supersaturated solution's crystallization propensity, more so in the case of the optimally tuned AGS. This study demonstrates the significance of simulating absorption of drug at a physiological rate during dissolution studies, especially to predict the performance of formulations of BCS-II drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

Advanced compartmental absorption and transit (ACAT) based computational models have become increasingly popular in the industry for predicting oral drug product performance. However, due to its complexity, some compromises have been made in practice, and the stomach is often assigned as a single compartment. Although this assignment worked generally, it may not be sufficient to reflect the complexity of the gastric environment under certain conditions. For example, this setting was found to be less accurate in estimating stomach pH and solubilization of certain drugs under food intake, which leads to a misprediction of the food effect. To overcome the above, we explored the use of a kinetic pH calculation (KpH) for the single-compartment stomach setting. Several drugs have been tested with the KpH approach and compared with the default setting of Gastroplus. In general, the Gastroplus prediction of food effect is greatly improved, suggesting this approach is effective in improving the estimation of physicochemical properties related to food effect for several basic drugs by Gastroplus. [ABSTRACT FROM AUTHOR]

Development of prodrugs is a useful strategy to overcome some disadvantages of candidate drugs. Recently, we established a systematic approach to selecting appropriate prodrugs, and validated the utility of this approach using oseltamivir analogues. In this study, the utility of the approach was further examined using candesartan cilexetil and 20 kinds of its analogues having various types of side chain as model compounds. Log D values of analogues (2.5 to 4.7) were higher than that of candesartan (1.0), their active metabolite, and the results were reasonable for the purpose of improving permeability of candesartan. The analogues tended to be more soluble in artificial intestinal fluids than in artificial gastric fluid, owing to their acidic physicochemical characteristics. Their membrane permeabilities were not correlated with log D values, which can be attributed to the metabolism in Caco-2 cells used in this system. In human hepatocytes and enterocytes, 11 out of the 20 analogues were immediately hydrolyzed to candesartan, and species differences were observed in the hydrolysis efficiency. This study confirmed the utility of the systematic approach for selection of appropriate prodrugs that could be proceeded to in vivo pharmacokinetics study, with selection of suitable experimental animals. [ABSTRACT FROM AUTHOR]

For decades, there has been a growing interest in injectable subcutaneous formulations to improve the absorption of drugs into the systemic circulation and to prolong their release over a longer period. However, fluctuations in the blood plasma levels together with bioavailability issues often limit their clinical success. This warrants a closer look at the performance of long-acting depots, for example, and their dependence on the complex interplay between the dosage form and the physiological microenvironment. For this, biopredictive performance testing is used for a thorough understanding of the biophysical processes affecting the absorption of compounds from the injection site in vivo and their simulation in vitro. In the present work, we discuss in vitro methodologies including methods and media developed for the subcutaneous route of administration on the background of the most relevant absorption mechanisms. Also, we highlight some important knowledge gaps and shortcomings of the existing methodologies to provide the reader with a better understanding of the scientific evidence underlying these models. [ABSTRACT FROM AUTHOR]

Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for pharmacokinetic studies in human volunteers to appraise the bioequivalence of immediate-release (IR) oral, solid dosage forms containing levocetirizine dihydrochloride was investigated, using data from the literature and in-house testing. Levocetirizine's solubility and permeability properties, as well as its dissolution from commercial products, its therapeutic uses, therapeutic index, pharmacokinetics and pharmacodynamic traits, were reviewed in accordance with the BCS, along with any reports in the literature about failure to meet bioequivalence (BE) requirements, bioavailability issues, drug-excipient interactions as well as other relevant information. The data presented in this monograph unequivocally point to classification of levocetirizine in BCS Class 1. For products that are somewhat supra-equivalent or somewhat sub-equivalent, clinical risks are expected to be insignificant in light of levocetirizine's wide therapeutic index and unlikelihood of severe adverse effects. After careful consideration of all the information available, it was concluded that the BCS-based biowaiver can be implemented for products which contain levocetirizine dihydrochloride, provided (a) the test product comprises excipients that are typically found in IR oral, solid drug products that have been approved by a country belonging to or associated with ICH and are used in quantities that are typical for such products, (b) data supporting the BCS-based biowaiver are gathered using ICH-recommended methods, and (c) all in vitro dissolution requirements specified in the ICH guidance are met by both the test and comparator products (in this case, the comparator is the innovator product). [ABSTRACT FROM AUTHOR]

This work describes the potential applicability of the BCS-based Biowaiver to oral solid dosage forms containing Levamisole hydrochloride, an anthelmintic drug on the WHO List of Essential Medicines. Solubility and permeability data of levamisole hydrochloride were searched in the literature and/or measured experimentally. Levamisole hydrochloride is a highly soluble drug, but there is no clear evidence of high permeability in humans, indicating that it should provisionally be assigned to BCS class III. The biowaiver procedure would thus be applicable for solid oral dosage forms containing levamisole hydrochloride as the only active ingredient. Due to the lack of data in the literature regarding excipient effects on the bioequivalence of products containing levamisole, it is currently recommended that the products comply with the ICH and WHO guidelines: the test formulation should have the same qualitative composition as the comparator, contain very similar quantities of those excipients, and be very rapidly dissolving at pH 1.2, 4.5, and 6.8. However, for certain well-studied excipients, there appears to be opportunity for additional regulatory relief in future versions of the ICH BCS Guidance M9, such as not requiring that the quantities of these common excipients in the test and comparator be the same. [ABSTRACT FROM AUTHOR]

A dissolution-permeation system has potential to provide insight into the kinetic contributions of dissolution and permeation to overall drug absorption. The goals of the study were to characterize a dissolution-hollow fiber membrane (D-HFM) system and compare its resulting in vitro drug permeation constants (K p ′) to in vivo clinical permeation constants (k p), for four drugs in various Biopharmaceutics Classification System (BCS) classes. Model predictions for D-HFM were made based on derived mixing tank (MT) and complete radial (CRM) flow models and independent measurement of membrane permeability. Experimental D-HFM studies included donor flow rate and donor volume sensitivity studies, and drug permeation profile studies. Additionally, for the four drugs, K p ′ from D-HFM system was compared to (k p) from literature, as well as K p ′ values from side-by-side diffusion cell and dissolution/Caco-2 system. Results show progressive D-HFM system development as a dissolution-permeation tool. Results indicated that D-HFM models using MT or CRM provided close agreement between predicted and observed drug permeation profiles. Drug permeation in D-HFM system was volume dependent, as predicted. Favorably, more drug permeated through the D-HFM system (10–20% in 60 min) compared to side-by-side diffusion cell (1%) and dissolution/Caco-2 system (0.1%). K p ′ from D-HFM system was also closer to in vivo k p ; the two other in vitro models showed lower K p ′. Overall, studies reflect that HFM module has potential to incorporate drug permeation into the in vitro assessment of in vivo tablet and capsule performance. [ABSTRACT FROM AUTHOR]

The gastrointestinal uptake of macrocyclic compounds is not fully understood. Here we applied our previously validated integrated system based on machine learning and conformal prediction to predict the passive fraction absorbed (f a), maximum fraction dissolved (f diss), substrate specificities for major efflux transporters and total fraction absorbed (f a,tot) for a selected set of designed macrocyclic compounds (n = 37; MW 407-889 g/mol) and macrocyclic drugs (n = 16; MW 734-1203 g/mole) in vivo in man. Major aims were to increase the understanding of oral absorption of macrocycles and further validate our methodology. We predicted designed macrocycles to have high f a and low to high f diss and f a,tot , and average estimates were higher than for the larger macrocyclic drugs. With few exceptions, compounds were predicted to be effluxed and well absorbed. A 2-fold median prediction error for f a,tot was achieved for macrocycles (validation set). Advantages with our methodology include that it enables predictions for macrocycles with low permeability, Caco-2 recovery and solubility (BCS IV), and provides prediction intervals and guides optimization of absorption. The understanding of oral absorption of macrocycles was increased and the methodology was validated for prediction of the uptake of macrocycles in man. [ABSTRACT FROM AUTHOR]

For injectable biopharmaceuticals, the subcutaneous route of administration is increasingly preferred over intravenous administration. However, one of the challenges in the development of subcutaneously administered biopharmaceuticals is a reduced bioavailability, which is difficult to predict. Since animal models do not reliably reflect bioavailability in patients, in vitro models could help to develop drug candidates. The purpose of this study was to evaluate a versatile set of in vitro tools for their suitability to predict bioavailability of biopharmaceuticals after subcutaneous administration. We examined seven commercially available biopharmaceuticals using three instruments, i.e., the Subcutaneous Injection Site Simulator (Scissor), the Osmomat 050, and a dialysis system using three artificial extracellular matrices, two dissolution apparatuses, i.e., the USP4 and the USP7, and two evaluation tools, i.e., the affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) and the Developability Index (DI). Results were evaluated for their usefulness to predict the bioavailability and other pharmacokinetic parameters in humans using the Pearson correlation. None of the tested instruments and methods could reliably approximate bioavailability. Only pressure values derived with the Osmomat 050 instrument correlated with C max with a Pearson correlation coefficient greater than 0.8. No single in vitro method confidently predicted the bioavailability in humans. We only found a correlation to maximum plasma concentration values for one of the tested approaches. However, a more focused evaluation would be necessary to confirm our findings and test combinations of orthogonal methods that may improve the confidence of such a prediction [ABSTRACT FROM AUTHOR]

The present monograph discusses the possibility of BCS-based biowaivers for immediate release pharmaceutical products containing raltegravir potassium, which is used to treat human immunodeficiency virus (HIV) infections. Raltegravir potassium can be assigned to BCS class II or IV since this compound has low solubility and uncertain permeability. Therefore, according to the ICH M9 guideline, it is not recommended to apply BCS-based biowaiver to approval of immediate release solid dosage forms of raltegravir potassium, either for new generic versions or when moderate to major changes in composition and/or the manufacturing method of the product are made., Competing Interests: Conflict of Interest This article is a part of the project of the Focus Group BCS & Biowaiver. The contents of this monograph are based on the data available in the literature and represent the scientific opinion of the authors but not necessarily the policies of regulatory authorities., (Copyright © 2024 American Pharmacists Association. All rights reserved.)

The aim of this study was to investigate the contributions of multiple transport mechanisms to the intestinal absorption of metformin, focusing on OCT3, PMAT, THTR2, SERT and OCTN2. We also assessed the impact of these transporters on the nonlinear absorption of metformin. Uptake studies with MDCKII cells expressing OCT3, PMAT, THTR2 or SERT confirmed that metformin is a substrate of these transporters. Decynium22 strongly inhibited metformin uptake mediated by all the transporters. 7-Cyclopentyl inhibited OCT3- and THTR2-mediated uptake of metformin. AG835, thiamine and paroxetine specifically inhibited PMAT-, THTR2- and SERT-mediated uptake of metformin, respectively. Using these inhibitors, the relative contributions of OCT3, PMAT, THTR2, SERT, OCTN2 and others to the intestinal permeation of metformin across Caco-2 cells were estimated to be 9.77%, 9.68%, 22.2%, 1.52%, 0% and 0.66%, respectively. Concentration-dependent analysis of metformin uptake by Caco-2 cells revealed nonlinear kinetics with the similar K m(app) value to the value for THTR2. Further in situ absorption study demonstrated that rat intestinal permeability of metformin was significantly decreased in the presence of decynium22, 7-cyclopentyl and thiamine. The present study indicated that THTR2 is the major determinant of the nonlinear absorption of metformin, although multiple transport mechanisms contribute to its intestinal absorption. [ABSTRACT FROM AUTHOR]

The transient absorption of two skin care agents, niacinamide (nicotinamide, NA) and methyl nicotinate (MN), solvent-deposited on ex vivo human skin mounted in Franz diffusion cells has been analyzed according to a new variation on a recently published mechanistic skin permeability model (Yu et al. 2020. J Pharm Sci 110:2149-56). The model follows the absorption and evaporation of two components, solute and solvent, and it includes both a follicular transport component and a dissolution rate limitation for high melting, hydrophilic solids deposited on the skin. Explicit algorithms for improving the simulation of transient diffusion of solvent-deposited solids are introduced. The simulations can account for the ex vivo skin permeation time course of both NA and MN over a dose range exceeding 4.5 orders of magnitude. The model allows one to describe on a mechanistic basis why the percutaneous absorption rate of NA is approximately 60-fold lower than that of its lower melting, more lipophilic analog, MN. It furthermore suggests that MN perturbs stratum corneum barrier lipids and increases their permeability while NA does not, presenting a challenge to molecular modelers engaged in simulating biological lipid barriers. [ABSTRACT FROM AUTHOR]

A quantitative understanding of the dose dependence of topical delivery is important to cosmetic and dermatological product development and to risk assessment for hazardous chemicals contacting the skin. Despite considerable research, predictive capability in this area remains limited. To this end we conducted an experimental skin absorption study of two closely related skin care agents, niacinamide (nicotinamide, NA) and methyl nicotinate (MN), and analyzed the results quantitatively using a transient diffusion model described separately (Yu et al. submitted for publication). Radiolabeled test compounds were solvent-deposited onto ex vivo human skin mounted in Franz diffusion cells over a dose range exceeding 4.5 orders of magnitude, and permeation was measured over a 1-4 day period. At low doses, the permeation rate of NA was approximately 60-fold lower than that of its lower melting, more lipophilic analog, MN; at high doses an even greater difference was observed. The difference can be qualitatively explained based on higher lipid solubility and lower crystallinity of MN relative to NA. Dissolution-limited mass transfer through a lipid layer at the SC surface is suggested. Relevance of the results to practical skin care formulations was confirmed by a parallel study of NA in an o/w emulsion. [ABSTRACT FROM AUTHOR]

A physiologically based biopharmaceutics model (PBBM) was developed to support formulation development of ribociclib, an orally bioavailable selective CDK4/6 inhibitor. Ribociclib is a weak base with moderate permeability and complete in vitro dissolution under stomach pH. GastroPlus™ was used to simulate the pharmacokinetics (PK) in healthy volunteers after capsule dosing. Simulations showed rapid, complete dissolution in human stomach without intestinal precipitation and with permeation-controlled absorption. Permeability was identified as controlling the systemic exposure. PBBM predicted bioequivalence (BE) between capsule and tablet in healthy volunteers, despite non-similarity between in vitro dissolution kinetics (f2<50). BE was verified in a clinical study. Then virtual bioequivalence (VBE) simulations predicted comparable PK in cancer patients between capsule and tablet of commercial batch, which was also confirmed in a clinical study. Finally, virtual trial simulations using virtual batches with slower dissolution were used to define an in vitro BE safe-space for tablets, where BE is expected. PBBM can identify drugs with permeability-controlled absorption for which formulation optimization can focus more on manufacturability rather than dissolution. PBBM can be used to predict BE study outcomes, define clinically relevant specification and BE safe-space, superseding dissolution similarity f2 criteria. [ABSTRACT FROM AUTHOR]

Azithromycin is an antibiotic listed in the essential list of medicines for adults and pediatrics. Conflicting evidence has been found regarding azithromycin classification according to the Biopharmaceutics classification system (BCS). The purpose of this study was to identify the critical variables that influence the oral absorption of azithromycin in adults and pediatrics. Azithromycin solubility and dissolution studies (oral suspension) were performed in buffers and biorelevant media simulating the fasted and fed gastrointestinal tract. A PBPK model was developed for azithromycin for healthy adult volunteers and pediatrics (Simcyp® v18.2) informed by in vitro solubility and dissolution studies to predict drug performance after administration of azithromycin as an oral suspension. The developed PBPK model predicted azithromycin plasma concentrations-time profiles after administration of an oral suspension to adults and pediatrics. Sensitivity analysis of solubility vs dose suggests that absorption is independent of solubility within the therapeutic dose range in both adults and pediatrics. The developed PBPK model for adults and pediatrics was consistent with the mechanism of permeation through the intestinal membrane (passive and active processes) being the rate-limiting step of azithromycin's absorption. The physiologically based approach proposed was shown to be useful to determine the factors controlling drug absorption in adults and pediatrics. [ABSTRACT FROM AUTHOR]

The improvement effect of the combined use of spermine (SPM), a polyamine, with sodium taurocholate (STC) on the pulmonary drug absorption was investigated utilizing poorly absorbable drugs with various molecular sizes in rats. The pulmonary absorption of rebamipide, a low molecular but poorly absorbable drug after oral administration, was significantly improved by the combined use of SPM with STC (SPM-STC formulation), while poly- L-lysine did not show a significant change in rebamipide absorption from the lungs. Furthermore, the safety of the SPM-STC formulation for the lungs was assessed in rats by the histopathological study and any local toxicity was not observed while poly-L-lysine, a typical chemical causing the toxicity for the epithelial cells, provided several histopathological changes. In addition, the SPM-STC formulation significantly improved the pulmonary absorption of fluorescein isothiocyanate dextran 4 (FD-4, Mw ca 4000) and interferon-α (IFN-α, Mw ca 25,000) as well. Our present results clearly indicated that the SPM-STC formulation significantly improved the pulmonary absorption of poorly absorbable small and large molecular drugs without any harmful effects on the lungs. Therefore, the SPM-STC formulation would be a useful one for the pulmonary absorption of drugs, specifically macromolecular ones, which are very difficult to be absorbed after oral administration. [ABSTRACT FROM AUTHOR]

Acid-reducing agents (ARAs) are the most commonly used medicines to treat patients with gastric acid-related disorders. ARA administration results in an elevation of intragastric pH and eases symptoms such as acid reflux. However, this effect could also lead to a reduction in the absorption of some co-administered oral medications (i.e. weakly basic drugs) by decreasing their gastric solubility. This in turn can result in a significant reduction of the efficacy of the co-administered oral medications. In order to address this problem, substantial efforts in translational modeling and the development of predictive in-vitro assays to better forecast the effect of ARA on oral absorption are conducted in the pharmaceutical industry. Despite these efforts, it remains challenging to predict the impact of ARAs on co-administered drugs. In this study, we evaluated the utility of Triskelion's Gastro-Intestinal Model (Tiny-TIM) in predicting ARA effect on twelve model drugs whose in-vivo data are available. The Tiny-TIM prediction of the ARA effect matched the observed effect of ARA co-administration in humans for the 12 model compounds. In summary, Tiny-TIM is a very reliable and promising GI model to successfully predict the nature of DDI when ARAs are co-administered with the drug of interest. [ABSTRACT FROM AUTHOR]

The physiological properties of the gastrointestinal tract, such as pH, fluid volume, bile salt concentration, and gastrointestinal transit time, are highly variable in vivo. These properties can affect the dissolution and absorption of a drug, depending on its properties and formulation. The effect of gastrointestinal physiology on the bioperformance of a drug was studied in silico for a delayed-release pantoprazole tablet and an immediate-release dolutegravir tablet. Physiologically based absorption models were developed and virtual clinical trials were performed. Reasons for the variability in drug bioperformance between subjects were investigated, taking into account differences in gastrointestinal tract characteristics, pharmacokinetic parameters, and additional parameters (e.g., permeability). Default software parameters describing gastrointestinal physiology in the fasted and fed states, and variation in these parameters, were altered to match variability in these parameters reported in vivo. The altered model physiologies better described the variability of gastrointestinal conditions, and therefore the results of virtual trials using these physiologies are likely to be more relevant in vivo. With such altered gastrointestinal physiologies used to develop models, it is possible to obtain additional knowledge and improve the understanding of subject-formulation interactions. [ABSTRACT FROM AUTHOR]

This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters.

The estimation of the extent of absorption of drug candidates intended for oral drug delivery is an important selection criteria in drug discovery. The use of cell-based transwell assays examining flux across cell-monolayers (e.g., Caco-2 or MDCK cells) usually provide satisfactory predictions of the extent of absorption in vivo. These predictions often fall short of expection for molecules outside the traditional low molecular weight property space. In this manuscript the transwell permeability assay was modified to circumvent potential issues that can be encountered when evaluating the aforementioned drug molecules. Particularly, the addition of albumin in the acceptor compartment to reduce potential binding to cells and the acceptor compartment, improved the predictive power of the assay. Cellular binding and lysosomal trapping effects are significantly reduced for larger molecules, particularly lipophilic bases under these more physiological conditions, resulting in higher recovery values and a better prediction power. The data indicate that lysosomal trapping does not impact the rate of absorption of lipophilic bases in general but is rather an exception. Finally, compounds believed to permeate by passive mechanisms were used in a calibration curve for the effective prediction of the fraction absorbed of molecules of interest in current medicinal chemistry efforts. [ABSTRACT FROM AUTHOR]

This study aimed to prepare a nanoemulsion vehicle to improve the oral bioavailability of hesperetin. The pseudo-ternary phase diagrams and the RSM were used to optimize nanoemulsion parameters. Compared with hesperetin suspension, the AUC 0-t and C max of nanoemulsion were increased by 5.67-fold and 2.64-fold, respectively. The proportion of lymphatic transport reached 87.72%, the cumulative absorption amount of jejunum, ileum, and duodenum increased by 1.1-fold, 1.92-fold, and 1.5-fold, respectively. The results implied that hesperetin nanoemulsion could effectively improve the bioavailability of hesperetin by increasing lymphatic transport and enhancing intestinal permeability. Therefore, nanoemulsion is a potential method to improve the bioavailability of hesperetin, which has strong practicability. [ABSTRACT FROM AUTHOR]

Topical pain relief products differ in the type of drug, concentration, and formulation. All these factors influence the drug transit through the skin barrier, and its eventual retention in the skin as a reservoir for subsequent release. In addition, the drug potency can be different, which is important for the product efficacy. We studied here ex vivo human skin permeation and retention of five over-the-counter NSAID gels containing 2.32% diclofenac (DIC) and 5–10% etofenamate (ETF). The potency of the permeated/retained drug amounts were compared using a composite parameter, the Index of Relative Topical Anti-inflammatory Activity (IRTAA), which is calculated as the product of the skin permeation/retention and the drug relative potency. The IRTAAs of the DIC gel were 94–667-fold higher and 72–208-fold higher for transdermal delivery and skin retention, respectively, than IRTAAs of the ETF gels. These superior IRTAAs indicate that DIC delivered by this topical formulation would achieve a higher bioactivity and would form a potent drug reservoir relevant for its subsequent long-lasting release. [ABSTRACT FROM AUTHOR]

A recently published mechanistic skin permeability model (Kasting et al., 2019. J Pharm Sci 108 :337-349) that included a follicular diffusion pathway has been extended to describe transient diffusion and finite dose applications. The model follows the disposition of two components, solute and solvent, so that solvent deposition processes can be explicitly represented. Experimentally-calibrated permeability characteristics of the follicular pathway leading to the permeation of highly hydrophilic permeants are further refined. Details of the refinements and a comparison with the earlier model using two large experimental datasets are presented. An example calculation shows the marked difference between the time scales for achievement of near steady-state diffusion for large hydrophilic and lipophilic compounds, with the former being more than 100-fold faster than the latter. However, the true steady state for the hydrophilic compound is not reached until much later due to the very slow filling of the corneocyte phase. [ABSTRACT FROM AUTHOR]

Membrane permeation enhancers have received significant attention in recent years for enabling the oral absorption of poorly permeable drug molecules. In this study, we investigated the ability of His-Ala-Val (HAV) and Ala-Asp-Thr (ADT) peptides derived from the extracellular-1 (EC1) domain of E-cadherin proteins to increase the paracellular permeation and intestinal bioavailability of the poorly permeable model macromolecule, fluorescein-isothiocyanate dextran with average molecular weight 4000 (FD4). The in vitro enzymatic stability of linear and cyclic E-cadherin peptides was characterized under simulated gastric and intestinal conditions, and the cyclic E-cadherin peptides, HAVN1 and ADTC5, which demonstrated excellent stability in vitro , were advanced to in vivo intestinal instillation studies and compared against the established surfactant membrane permeation enhancer, sodium caprate (C 10). Cyclic HAVN1 and ADTC5 peptides increased FD4 bioavailability by 7.2- and 4.4-fold compared to control, respectively (not statistically significant). In contrast, C 10 provided a statistically significant 10.7-fold relative bioavailability enhancement for FD4. Importantly, this study represents the first report of cyclic E-cadherin peptides as intestinal membrane permeation enhancers. The findings described herein demonstrate the potential of enzymatically stabilized cyclic E-cadherin peptides for increasing poorly permeable drug absorption via the oral route. [ABSTRACT FROM AUTHOR]

Absorption via the intestinal lymphatic system is known to be important for some highly lipophilic compounds, and can be associated with unique pharmacokinetic properties due to evasion of hepatic first-pass metabolism. This work aimed to develop a physiologically-based pharmacokinetic model incorporating the role of lymphatic transport in a physiologically-based, mechanistic oral absorption model, using halofantrine as a model compound. Simcyp V19 was used for model development; oral absorption was characterized using the multi-layer gut wall (M-ADAM) model, and the model was constructed and verified using parameters derived from in vitro experiments and clinical PK data. The final model appeared to adequately capture halofantrine pharmacokinetics in the fasted state and the magnitude of the effect of food on halofantrine total exposure; the effect of food on peak exposure was slightly underpredicted, which may be due to transient post-prandial changes in protein binding. The model simulated halofantrine fraction absorbed (f a) via the lymph in the fed state was 0.26, representing 62% of the increase in f a in the fed state over fasting. This work demonstrates that a PBPK modeling approach can be used to mechanistically describe oral absorption incorporating intestinal lymphatic transport. [ABSTRACT FROM AUTHOR]

Garcinia cambogia extract (GCE)/(−) – hydroxycitric acid (HCA) has been identified as a potential antiobesity agent. However, controversial clinical trial results have been published on its biological effect and poor pharmacokinetic (PK) information increases its dubious efficacy. The aim of this study was to determine the main PK parameters of GCE/HCA in healthy women, and to evaluate food effects on HCA absorption. Healthy women ages 21–41 years with body mass index (BMI; kg/m2) 20.29–25.82 participated in a phase I, open-label, randomized, single-dose, cross-over study. In the fasted- and fed-conditions subjects received 1500/750 mg of GCE/HCA under 8 h of fasting. In the fed-period was given a high calorie breakfast (~600 calories) after dosing. Plasma HCA concentrations were substantially reduced in fed-state. Peak plasma concentration (C max) and area under the curve of time-concentration (AUC 0–10h) were 3-fold and 2-fold lower (p < 0.001, 0.01) in fed-condition, respectively. Higher volume of distribution (Vd/F) and clearance (Cl/F) were achieved in fed state, probably due to the lower fraction (F) of HCA absorbed induced by food effect. Large inter-individual variations were observed for the main pharmacokinetics parameters in both periods. These findings suggest that HCA might suffer an active absorption uptake and intense adsorption on food. • Extended time to reach peak plasma HCA concentration. • Substantial food-effect on HCA absorption. • High inter-individual variation of plasma HCA concentration. • Suggestive active uptake and adsorption of HCA on food. [ABSTRACT FROM AUTHOR]

3D cultures of primary human hepatocytes (PHH) are emerging as a more in vivo-like culture system than previously available hepatic models. This work describes the characterisation of drug metabolism in 3D PHH spheroids. Spheroids were formed from three different donors of PHH and the expression and activities of important cytochrome P450 enzymes (CYP1A2, 2B6, 2C9, 2D6, and 3A4) were maintained for up to 21 days after seeding. The activity of CYP2B6 and 3A4 decreased, while the activity of CYP2C9 and 2D6 increased over time (P < 0.05). For six test compounds, that are metabolised by multiple enzymes, intrinsic clearance (CL int) values were comparable to standard in vitro hepatic models and successfully predicted in vivo CL int within 3-fold from observed values for low clearance compounds. Remarkably, the metabolic turnover of these low clearance compounds was reproducibly measured using only 1–3 spheroids, each composed of 2000 cells. Importantly, metabolites identified in the spheroid cultures reproduced the major metabolites observed in vivo, both primary and secondary metabolites were captured. In summary, the 3D PHH spheroid model shows promise to be used in drug discovery projects to study drug metabolism, including unknown mechanisms, over an extended period of time. [ABSTRACT FROM AUTHOR]

This issue of the Journal of Pharmaceutical Sciences is dedicated to Professor Per Artursson and the groundbreaking contributions he has made and continues to make in the Pharmaceutical Sciences. Per is one of the most cited researchers in his field, with more than 30,000 citations and an h-index of 95 as of September 2020. Importantly, these citations are distributed over the numerous fields he has explored, clearly showing the high impact the research has had on the discipline. We provide a short portrait of Per, with emphasis on his personality, driving forces and the inspirational sources that shaped his career as a world-leading scientist in the field. He is a curious scientist who deftly moves between disciplines and has continued to innovate, expand boundaries, and profoundly impact the pharmaceutical sciences throughout his career. He has developed new tools and provided insights that have significantly contributed to today's molecular and mechanistic approaches to research in the fields of intestinal absorption, cellular disposition, and exposure-efficacy relationships of pharmaceutical drugs. We want to celebrate these important contributions in this special issue of the Journal of Pharmaceutical Sciences in Per's honor. [ABSTRACT FROM AUTHOR]

NSAIDs such as celecoxib and sulindac play a critical role in the treatment of colorectal cancer, yet it is not understood how sufficiently high concentrations are reached in colonic tissue. We previously demonstrated that an incomplete small intestinal absorption of celecoxib enables gut driven drug accumulation in caecal tissue, which is most likely needed for inducing remission. However, a multistage dissolution experiment suggested a more extensive absorption of sulindac relative to celecoxib, though still incomplete. To study whether caecal accumulation of sulindac is solely plasma driven or also gut driven, we performed an exploratory clinical study in healthy volunteers. After intake of a tablet of sulindac (200 mg; Arthrocine), two colonoscopies (1.0–2.5 h, and 6.0–7.5 h after drug intake) were performed to assess concentrations of sulindac and metabolites in plasma, caecal tissue and caecal contents. We observed that sulindac, even without the use of a colon-targeted delivery strategy, can arrive at the colonic lumen due to incomplete absorption and biliary excretion, and that the microbiota can catalyse the production of sulindac sulfide, which then accumulates in a high and local manner in the colonic tissue. These data can be relevant for drug development in the treatment of colorectal adenomas and cancer. [ABSTRACT FROM AUTHOR]

The aim of this work was to develop a new in vitro lipolysis-permeation model to predict the in vivo absorption of fenofibrate in self-nanoemulsifying drug delivery systems (SNEDDSs). More specifically, the in vitro intestinal lipolysis model was combined with the mucus-PVPA (Phospholipid Vesicle-based Permeation Assay) in vitro permeability model. Biosimilar mucus (BM) was added to the surface of the PVPA barriers to closer simulate the intestinal mucosa. SNEDDSs for which pharmacokinetic data after oral dosing to rats was available in the literature were prepared, and the ability of the SNEDDSs to maintain fenofibrate solubilized during in vitro lipolysis was determined, followed by the assessment of drug permeation across the mucus-PVPA barriers. The amount of drug solubilized over time during in vitro lipolysis did not correlate with the AUC (area under the curve) of the plasma drug concentration curve. However, the AUC of the drug permeated after in vitro lipolysis displayed a good correlation with the in vivo AUC (R2 > 0.9). Thus, it was concluded that the in vitro lipolysis–mucus-PVPA permeation model, simulating the physiological digestion and absorption processes, was able to predict in vivo absorption data, exhibiting great potential for further prediction of in vivo performance of SNEDDSs. [ABSTRACT FROM AUTHOR]

Biopharmaceutics Classification System and Biopharmaceutics Drug Distribution Classification System are complimentary, not competing, classification systems that aim to improve, simplify, and speed drug development. Although both systems are based on classifying drugs and new molecular entities into four categories using the same solubility criteria, they differ in the criterion for permeability and have different purposes. Here, the details and applications of both systems are reviewed with particular emphasis of their role in drug development.

Emodin exerts anti-inflammatory and anti-cancer effects. However, its poor water solubility limits development into a pharmaceutical product. Although an emodin-nicotinamide cocrystal (ENC) with improved dissolution rate was proposed as a potential candidate, crystallization back to emodin after dissolution diminished the advantage of the cocrystal approach. The objectives of this study were to identify a crystallization inhibitor to maintain the emodin supersaturation generated by ENC dissolution, and to examine its effect on oral pharmacokinetics of ENC. Among various polymers, polyvinylpyrrolidone K30 (PVP) was the most effective solubilizer and crystallization inhibitor. The solubility of ENC in a simulated intestinal fluid containing 1.5% PVP was 2-fold higher than that of emodin. However, comparison of oral pharmacokinetics in rats between ENC and emodin did not reflect such improved solubility of ENC in vitro relative to emodin. Instead, the plasma concentrations of a major metabolite of emodin showed a positive correlation with in vitro dissolution results, suggesting rapid gastrointestinal metabolism of emodin during absorption. In conclusion, PVP contributes to enhanced dissolution rates of ENC and inhibits crystallization of emodin in vivo, so that more metabolites can be formed and absorbed. Therefore, a metabolism inhibitor would be necessary to improve the oral bioavailability of emodin further. [ABSTRACT FROM AUTHOR]

The partition rate of 2 model compounds, 2-naphthol (NAP) and ritonavir (RTV), across the water-octanol (W/O) interface was determined from aqueous solutions with and without the presence of a variety of common pharmaceutical excipients. The NAP molecule was present as either a unionized species in the phosphate buffer solution or as an anion in 0.01 M NaOH solution while RTV was present as dications in 0.1 M HCl. Excipients examined include different type of polymers (e.g., PVP-VA, HPMC, HPMCAS, PVP, PEG 8000), small molecules (e.g., glucose, lactose, maltoheptaose), and surfactants (e.g., Tween 80 and SDS). A noticeable to significant reduction of the partition rate of both NAP and RTV across the W/O interface was observed with aqueous media containing 0.01–0.1 μg/mL polymers including PVP-VA, HPMC, and HPMCAS. Reduction of NAP and RTV partition rate associated with such extremely low concentration of polymers in the aqueous media affirms the presence of a surface excess of adsorbed excipients at the W/O interface. Pi values of NAP and RTV across the W/O interface are found to be sensitive to (1) the molecule surface area, molecular weight and the degree of the polymerization of these pharmaceutical excipients, and (2) the ionization state of the model compound. [ABSTRACT FROM AUTHOR]

To increase the success rate in development of prodrugs, we sought to establish a systematic in vitro method to appropriately select candidate prodrugs. Physicochemical/biopharmaceutical properties of 21 commercially available prodrugs (16 with improved membrane permeability of pharmacologically active metabolites and 5 with improved solubility) and their active metabolites were characterized in terms of solubility in artificial intestinal fluids and membrane permeability using Caco-2 cells. Their in vitro metabolic profiles were also evaluated, using human and animal enterocytes, hepatocytes, and sera. Log D values of prodrugs with improved membrane permeability were higher than those of their active metabolites, whereas those of prodrugs with improved aqueous solubility were lower than those of active metabolites. The prodrugs with improved aqueous solubility were highly soluble in artificial intestinal fluids. All prodrugs were efficiently converted to active metabolites with human matrices, whereas some were not with dog or monkey matrices. This study demonstrated that physicochemical/biopharmaceutical properties could be useful information to facilitate design of prodrugs and for selection of candidate prodrugs. Moreover, the in vitro evaluation of conversion efficiency to active metabolites would be helpful for selecting ideal prodrugs as well as appropriate animals for in vivo PK studies. [ABSTRACT FROM AUTHOR]

This article describes a new method of estimating the absorption rate constant (k a) of a 2-compartment model with extravascular administration, which is called an alternative method. The method was based on approximating the distribution and elimination phases of a 2-compartment model to the elimination phase of a one-compartment model. By using the model equation t max = ln k a − ln ( k 10 + k 12 ) k a − ( k 10 + k 12 ) , first, we obtained the peak time (t max) and the sum value of the first-order elimination rate constant (k 10) and the distribution rate constant (k 12), then the iterative method was used to obtain estimated value. And the estimation results were compared with the results obtained by the Loo-Riegelman and statistical moment methods and the factors affecting the estimation results of alternative method were explored. Finally, verification experiments were carried out with actual data in the literature. In general, a good estimation effect on the value of k a in the extravascular administration of the 2-compartment model was obtained by this method, with less errors compared with the commonly used 2 other methods (p < 0.05). Changes in k 12 , k 10 , k a , and another distribution rate constant (k 21) all influenced the estimation results. The alternative method also showed good results in estimating k a of compounds in the literature. [ABSTRACT FROM AUTHOR]

None of the physiologically based pharmacokinetic (PBPK) approaches using preclinical data show high predictability of human pharmacokinetic (PK) profiles for drugs affected by the intestinal first-pass effect. Here we report a novel PBPK approach that incorporated the findings of a permeation study using human induced pluripotent stem cell-derived intestinal epithelial cells (hiPSC-IECs) to predict human PK profiles after oral administration of drugs. In hiPSC-IECs, gene expression levels of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) are enhanced by rifampicin and 1,25-dihydroxyvitamin D 3. The permeability of 24 drugs (10 test drugs and 14 reference drugs), including CYP3A4 and P-gp substrates, correlated highly with gastrointestinal availability (F a × F g), and could be converted to the apparent absorption rate constant (k a, app) based on the correlation between F a × F g and in vivo k a of 27 drugs. The k a, app was input into the PBPK model which contained the optimized calculation processes of metabolism and tissue distribution. The absolute average fold error of PK parameters such as maximum plasma concentration and bioavailability for test drugs was less than 2, suggesting that human PK profiles could be predicted with high accuracy. Our robust PBPK approach enables quick decision-making in drug discovery based on human PK profiles. [ABSTRACT FROM AUTHOR]

Sodium caprate (C10) acts as an absorption enhancer. However, the absorption-enhancing effects of compounds with structures similar to C10 have not been characterized. In the present study, insulin was used as a model drug. We examined the effects of C10 and its related compounds on intestinal absorption of insulin using an in situ closed loop in rats. Insulin absorption was significantly enhanced by propylene glycol caprylate (Sefsol-218), a C10-related compound, after large intestinal administration. In addition, activity of lactate dehydrogenase did not increase in the intestinal epithelium in the presence of Sefsol-218 at concentrations equivalent to or lower than 1% (v/v). However, a significant increase in lactate dehydrogenase activity was observed in response to C10. These findings suggested that Sefsol-218 was safer than C10. Furthermore, mechanistic studies showed that increased membrane fluidity and loosening of tight junctions (TJs) might be underlying mechanisms by which this compound improved intestinal absorption of insulin. Furthermore, Sefsol-218 opened TJs by reducing the expression of claudin-4, which is a major TJ protein. These findings suggested that Sefsol-218 effectively enhanced intestinal insulin absorption without causing serious damage to the intestinal epithelium. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to characterize current biopharmaceutics modeling and simulation software regarding the prediction of the fraction of a dose absorbed (Fa) in humans. As commercial software products, GastroPlus™ and Simcyp® were used. In addition, the gastrointestinal unified theoretical framework, a simple and publicly accessible model, was used as a benchmark. The Fa prediction characteristics for a total of 96 clinical Fa data of 27 model drugs were systematically evaluated using the default settings of each software product. The molecular weight, dissociation constant, octanol-water partition coefficient, solubility in biorelevant media, dose, and particle size of model drugs were used as input data. Although the same input parameters were used, GastroPlus™, Simcyp®, and the gastrointestinal unified theoretical framework showed different Fa prediction characteristics depending on the rate-limiting steps of oral drug absorption. The results of the present study would be of great help for the overall progression of physiologically based absorption models. [ABSTRACT FROM AUTHOR]

There has been an increasing interest in accurate prediction of human pharmacokinetics of drug candidates to reduce cost and increase productivity during research and development. Modeling efforts have primarily focused on predicting drug absorption after oral administration because it is the most desired route for small molecule drug delivery. Despite significant progress in the field, the fraction of dose absorbed (Fa) is still considered to be a challenging parameter to predict. In recent years, compartment and transit models have become increasingly popular because of their effectiveness. A multicompartment plug flow–based model in which the stomach is assigned as a single compartment has been built. However, this model was found to be less accurate in estimating stomach solubilization of basic drugs under certain conditions and leads to false-negative results. Therefore, a modified multicompartment approach was developed by dividing the stomach into 4 compartments allowing the model to better mimic the physiological conditions. This approach was found to be more precise in estimating Fa for basic drugs compared to the previous approach. Based on this finding, it is believed the aforementioned approach should also be applicable to all compartmental-based models when similar issues are encountered. [ABSTRACT FROM AUTHOR]

Acid-reducing agents (ARAs) such as antacids, histamine-2 receptor antagonists, and proton pump inhibitors are widely prescribed in several disease states. In the case of a basic drug with pH-dependent solubility, concomitant administration with an ARA may reduce drug absorption and systemic exposure, potentially resulting in the loss of efficacy. Therefore, it is important to assess a drug's susceptibility to pH-dependent drug-drug interactions (DDIs) during drug development, to characterize the DDI with clinical studies (as needed), and include appropriate instructions in the label. Given the ability of physiologically based biopharmaceutics modeling (PBBM) to directly link pharmacokinetics with physiological parameters, compound and formulation properties, these models are well positioned to address the DDI effects of ARAs. In this article, we describe application of PBBM for biopharmaceutics risk assessment, and to guide formulation and clinical development strategies. Seven case studies from 5 pharmaceutical companies are presented demonstrating cross-industry experience in PBBM prediction of pH-dependent DDIs. These case studies are for BCS 2 and 4 compounds, with adequate clinical data to assess the accuracy of the predictions. Based on these examples, and previously published literature, we propose a pragmatic PBBM workflow to inform clinical development and regulatory decisions in ARA risk assessment. [ABSTRACT FROM AUTHOR]