Magnetic resonance imaging quantification of fasted state colonic liquid pockets in healthy humans

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or “pockets”. Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (∼8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean ± SEM) 11 ± 5 pockets of resting liquid with a total volume of 2 ± 1 mL (average). The colonic fluid peaked at 7 ± 4 mL 30 min after the water drink. This peak fluid was distributed in 17 ± 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of pockets of freely mobile liquid in the undisturbed colon of fasted humans after ingestion of a glass of water. Novel insights into the colonic fluid environment will be particularly relevant to improve our understanding and design of the in vivo performance of controlled release formulations targeted to the colon. The in vivo quantitative information presented here can be input into physiologically based mechanistic models of dissolution and absorption, and can be used in the design and set up of novel in vitro performance tools predictive of the in vivo environment

Drug Dissolution in Oral Drug Absorption:Workshop Report

The in-person workshop "Drug Dissolution in Oral Drug Absorption" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of "dissolved drug," particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.</p

Integrisani biofarmaceutski pristup u razvoju i karakterizaciji lekova: opšti koncept i primena

The importance of biopharmaceutical considerations in pharmaceutical development and drug characterization has been well recognized both by pharmaceutical industry and regulatory authorities as a tool to establish predictive relationships between drug product quality attributes (in vitro data) and its clinical performance (in vivo data). In the present paper, contemporary biopharmaceutics toolkit including in vivo predictive dissolution testing, Biopharmaceutics Classification System, physiologically based pharmacokinetic and biopharmaceutics modeling and simulation, in vitro-in vivo correlation and biowaiver, are reviewed with regards to relevant general principles and applicability. The recently introduced innovative strategy for patient-centric drug development using an integrated systems approach grounded in fundamental biopharmaceutics concepts, clinical insights and therapeutic drug delivery targets, described as Biopharmaceutics Risk Assessment Roadmap (BioRAM) is also presented. Further development in the field will benefit from joint efforts and exchange of knowledge and experiences between pharmaceutical industry and regulatory authorities for the common goal to accelerate development of effective and safe drug products designed in accordance with patients’ needs and expectations.Značaj biofarmaceutskih razmatranja u razvoju i karakterizaciji lekova s ciljem uspostavljanja korelacije i mogućnosti predviđanja odnosa između in vitropodataka, odnosno karakteristika kvaliteta leka i njegovog in vivoponašanja/kliničkog učinka, prepoznata je kako od strane farmaceutske industrije, tako i od strane odgovarajućih regulatornih tela. U radu je dat pregled savremenih biofarmaceutskih alata,uključujući prediktivno ispitivanje brzine rastvaranja lekovite supstance iz farmaceutskog oblika leka, Biofarmaceutski sistem klasifikacije, fiziološki zasnovano farmakokinetičko i biofarmaceutsko modelovanje i simulacije, in vitro-in vivokorelaciju i mogućnost izostavljanja in vivostudija bioekvivalencije (engl. biowaiver) iz aspekta opštih principa i mogućnosti primene u razvoju i karakterizaciji lekova.Predstavljena je i nedavno osmišljena inovativna strategija za razvoj leka usmerena ka pacijentu, uz primenu integrisanog sistemskog pristupa zasnovanog na osnovnim biofarmaceutskim konceptima, uvidu u kliničku situaciju i definisanim terapijskim ciljevima označena kao Plan aktivnosti za procenu biofarmaceutskog rizika (engl. Biopharmaceutics Risk Assessment Roadmap, BioRAM). Očekuje se da će daljem razvoju u ovoj oblasti najviše doprineti združene aktivnosti i razmena znanja i iskustava između farmaceutskih kompanija i regulatornih agencija sa zajedničkim ciljem da se ubrza razvoj efikasnih i bezbednihlekova dizajniranih u skladu sa potrebama i očekivanjima pacijenata

In Vitro Dissolution as a Tool for Formulation Selection: Telmisartan Two-Step IVIVC

The purpose of this investigation was todevelop an exploratory two-step level A IVIVC for threetelmisartan oral immediate release formulations, the referenceproduct Micardis, and two generic formulations (X1 and X2).Correlation was validated with a third test formulation, Y1.Experimental solubility and permeability data were obtained toconfirm that telmisartan is a class II compound under theBiopharmaceutic Classification System. Bioequivalence (BE)studies plasma profiles were combined using a previouslypublished reference scaling procedure. X2 demonstrated invivo BE, while X1 and Y1 failed to show BE due to the lowerboundary of the 90% confidence interval for Cmax being outsidethe acceptance limits. Average plasma profiles were deconvo-luted by the Loo-Riegelman method to obtain the oral fractions absorbed (fa ). Fractions dissolved (fdiss ) were obtained in severalconditions in USP II and USP IV apparatus, and later, the results were compared in order to find the most biopredictive model,calculating the f 2 similarity factor. The apparatus and conditions showing the same rank order than in vivo data were selected forfurther refinement of conditions. A Levy plot was constructed to estimate the time scaling factor and to make both processes,dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivobehavior of the different formulations of telmisartan employed the USP IV dissolution apparatus and a dissolution environmentwith a flow rate of 8 mL/min and a three-step pH change, from 1.2 to 4.5 and 6.8, with a 0.05% of Tween 80. Thus, theseconditions gave rise to a biopredictive dissolution test. This new model is able to predict the formulation differences indissolution that were previously observed in vivo, which could be used as a risk-analysis tool for formulation selection in futurebioequivalence trials

Biopredictive capability assessment of two dissolution/permeation assays, µFLUX™ and PermeaLoop™, using supersaturating formulations of Posaconazole

The majority of new drug entities exhibits poor water solubility and therefore enabling formulations are often needed to ensure sufficient in vivo bioavailability upon oral administration. Several in vitro tools have been proposed for biopredictive screening of such drug formulations to facilitate formulation development. Among these, combined dissolution/permeation (D/P) assays have gained increasing interest in recent years, since they are presumed to better predict the absorption behavior as compared to single-compartment dissolution assays. Moreover, especially for supersaturating formulations, it has been demonstrated that the presence of an absorption sink better mimics the intraluminal supersaturation performance. The present study aimed to investigate the biopredictive abilities of two in vitro D/P setups to predict intestinal supersaturation and systemic absorption of supersaturable systems. Experiments were performed with a µFLUX™ and PermeaLoop™ apparatus, respectively, which differ primarily in their volume-to-area ratios between donor compartment and membrane as well as in the type of biomimetic barrier. A two-stage dissolution protocol was adopted to mimic the transit from acidic stomach to more neutral intestinal fluids using biomimetic media. Three formulations of the weakly basic compound Posaconazole (PCZ), namely an acidified and a neutral suspension and an amorphous solid dispersion (ASD) tablet, were tested. Under the present conditions, and for the specific set of formulations studied here, PermeaLoop™ showed a better biopredictive ability for intestinal supersaturation and systemic absorption for the three formulations than the µFLUX™ D/P setup. Interestingly, minor modifications of the two-stage D/P protocol in terms of medium transfer rates from simulated gastric fluid (SGF) to fasted state simulated intestinal fluid (FaSSIF) had a substantial impact particularly on the permeation of the crystalline PCZ suspension (“acidified suspension”). The ASD tablet was less sensitive to gradual medium changes than the crystalline PCZ suspensions. The current study confirms the usefulness of D/P assays for formulation ranking of weakly basic compounds and supersaturating formulations.</p

Two-step in vitro-in vivo correlations: Deconvolution and convolution methods, which one gives the best predictability? Comparison with one-step approach.

Finding predictive dissolution tests and valid IVIVCs are essential activities in generic industry, as they can be used as substitutes of human bioequivalence studies. IVIVCs can be developed by two different strategies: a onestep approach or a two-step approach. The objectives of this work were to compare different deconvolution and convolution methods used in the development of two-step level A IVIVCs and to study if the relationship between the in vitro dissolution rate and the in vivo dissolution rate should guide the decision between using a two-step approach or a one-step approach during the development of a new IVIVC. When the in vitro and the in vivo dissolution rates had a linear relationship, valid and biopredictive two-step IVIVCs were obtained, although there was not a combination of deconvolution and convolution methods that could be named as the best one, as long as all the prediction errors for any combination were within the limits. It was not possible to obtain a valid two-step IVIVC when the relationship between dissolution rates was nonlinear, but the one-step approach was able to overcome this fact and it gave valid IVIVCs regardless of whether the relationship between dissolution rates was linear or non-linear

Can in vitro/in silico tools improve colonic concentration estimations for oral extended-release formulations? A case study with upadacitinib

Upadacitinib, classified as a highly soluble drug, is commercially marketed as RINVOQ®, a modified-release formulation incorporating hydroxypropyl methylcellulose as a matrix system to target extended release throughout the gastrointestinal (GI) tract. Our study aimed to explore how drug release will occur throughout the GI tract using a plethora of in vitro and in silico tools. We built a Physiologically-Based Pharmacokinetic (PBPK) model in GastroPlus™ to predict the systemic concentrations of the drug when administered using in vitro dissolution profiles as input to drive luminal dissolution. A series of in vitro dissolution experiments were gathered using the USP Apparatus I, III and IV in presence of biorelevant media, simulating both fasted and fed state conditions. A key outcome from the current study was to establish an in vitro-in vivo correlation (IVIVC) between (i) the dissolution profiles obtained from the USP I, III and IV methods and (ii) the fraction absorbed of drug as deconvoluted from the plasma concentration-time profile of the drug. When linking the fraction dissolved as measured in the USP IV model, a Level A IVIVC was established. Moreover, when using the different dissolution profiles as input for PBPK modeling, it was also observed that predictions for plasma Cmax and AUC were most accurate for USP IV compared to the other models (based on predicted versus observed ratios). Furthermore, the PBPK model has the utility to extract the predicted concentrations at the level of the colon which can be of utmost interest when working with specific in vitro assays

In vitro Tools for Biopharmaceutical Studies of Drug Formulations

I øjeblikket bliver en stigning mængde lægemidler, med svært opløselige lægemiddelstoffer godkendt til markedsføring. Avancerede formulering teknikker er nødvendige for tilstrækkelig absorption fra mange af disse lægemidler. Bioprædiktiv opløsningstest kan hjælpe med at vurdere optimale formuleringer eller forbedre forståelsen af absorptionen af lægemidlet under relevante fysiologiske forhold. Kombinerede opløsnings-/permeation tests er en type af bioprædiktive opløsningstest, der ofte kan give information om forskellige stadier af opløst stof der er til stede under opløsningen af et lægemiddelprodukt.Formålet med denne afhandling er at evaluere brugen af kombinerede opløsnings-/permeations tests af lægemidler som indeholder et svært opløseligt lægemiddelstof. Dette arbejde indebærer at sammenligne nogle af de mest almindeligt anvendte værktøjer. Samt at evaluere for hvilke lægemiddelprodukter hvor de kombinerede opløsnings-/permeations tests er mest relevant. I undersøgelser direkte på værktøjerne har er omrøring a 96-brønds plader og strukturen af lipid visikler i PermeaPad® barrieren blevet undersøgt. Derudover var andre undersøgelser mere specifikke i retning af at benytte kombinere opløsnings-/permeation teste til en mekanistisk forståelse af absorptionen af formuleringer indeholdende cyclodextriner, prodrugs eller nanosuspensioner.Konklusionen på denne afhandling er at kombinerede opløsnings-/permeations-værktøjer er nyttige til bedre at forstå absorptionsprocesserne for de fleste lægemidler som indeholder et dårligt opløseligt lægemiddelstof, da forskellige opløste stadier oftest spiller en væsentlig rolle i absorptionen af disse. Der er ikke noget opløsnings-/permeations-værktøj som er bedre på alle aspekter, og de specifikke spørgsmål der skal besvares ved opløsnings-/permeations forsøg bør altid overvejes når et værktøj skal vælges. Ofte vil ethvert opløsnings-/permeations-værktøj dog kunne give den nødvendige indsigt. Derfor kan det oftest være bedst bare at vælge det opløsnings-/permeations-værktøj der er nemmest at bruge under de givne omstændigheder.There is currently an increase in drug products containing a poorly soluble drug compound being introduced to the pharmaceutical market. Sufficient drug absorption from many of these drug products can not be obtained without the use of dissolution-enabling formulation techniques for the drug products. Biopredictive dissolution testing can help to assess optimal formulation or understanding of the absorption of the drug product under relevant physiological conditions. Combined dissolution/permeation tests are a type of biopredictive dissolution test that often can provide information about different dissolved species present during the dissolution of a drug product.This thesis aimed to evaluate the use of combined in vitro dissolution/permeation tests with drug products of poorly soluble drug compounds. This work involves comparing some of the most commonly used tools and evaluating which drug products combined dissolution/permeation testing might be found most relevant. Studies directly related to the investigation of some tools investigated the agitation of 96-well plates and the morphology of lipid vesicles in the PermeaPad® barrier. Meanwhile, other studies were more specific towards combining dissolution/permeation to a mechanistic understanding of the absorption of formulations containing cyclodextrins, prodrugs, or nanosuspensions.The dissertation concludes that combined dissolution/permeation tools are useful for better understanding the absorption processes of most drug products of poorly soluble drug compounds, as different dissolved species most often play a significant role in their absorption. There is no superior dissolution/permeation tool in all aspects, and the challenges should always be considered when picking a tool. However, often will any dissolution/permeation tool be able to provide the necessary insight, and the tool easiest to use in the given circumstances might just be used.<br/

BCS-based biowaivers : risks and opportunities

Bei peroral eingenommenen Arzneimitteln wird das Plasmakonzentrations-Zeit-Profil des aktiven Stoffes im Allgemeinen als Maß für die Wirksamkeit und Sicherheit des Arzneimittels angesehen. Bei Veränderungen an bestehenden Arzneimitteln oder der Entwicklung eines Generikums kann durch Bioäquivalenzstudien an gesunden Probanden untersucht werden, ob das Plasmakonzentrations-Zeit-Profil gleich bleibt. Auf eine solche Studie kann verzichtet werden (sog. Biowaiver), wenn ausreichend bewiesen ist, dass das Test- und das Referenzprodukt in vitro äquivalent sind. Die Möglichkeit für einen Biowaiver hängt von den Eigenschaften des aktives Stoffes und der Formulierung ab. Die vorliegende Doktorarbeit untersucht die internationalen (US, EU und WHO) regulatorischen Bedingungen für einen Biowaiver aus einer risikoorientierten Perspektive mit dem Ziel, neue Möglichkeiten für einen Biowaiver zu identifizieren. Offensichtlich sind die Bedingungen für einen Biowaiver weltweit verschieden. Unterschiedliche Definitionen der Löslichkeit eines Arzneistoffes können entscheidende Konsequenzen haben für die Daten die für den Nachweis der Bioäquivalenz nötig sind. Eine Harmonisierung der Kriterien durch die Zulassungsbehörden, akademische Welt und Industrie könnte die Anwendung des Biowaiveransatzes vereinfachen und die Zahl der klinischen Studien verringern. Das Verständnis der biopharmazeutischen Effekten von Hilfsstoffen könnte die Möglichkeiten für einen Biowaiver erweitern. Laktose wird zum Beispiel in sehr unterschiedlichen Mengen in vergleichbaren Tabletten und Kapseln mit Arzneistoffen aus unterschiedlichen Klassen des Biopharmaceutics Classification Systems (BCS) kombiniert. Daneben ist aus der Literatur bekannt, dass Laktose höchstens einen Effekt auf die Freisetzung des aktiven Stoffes hat und nicht auf andere Parameter. Daher könnte eine vergleichende In-vitro-Wirkstoff-Freisetzungsstudie ausreichend sein um eine Veränderung des Laktosegehaltes im zugelassenen Bereich zu unterstützen. Die Möglichkeiten der Anwendung von neuen Modellen für Biowaiver wurden anhand von Chitosan untersucht. Chitosan ist bekannt als ein potentieller Modulator der intestinalen Absorption. In einer klinischen Studie hatte Chitosan einen signifikant negativen Effekt auf auf die Maximalkonzentration (Cmax), den Zeitpunkt ihres Auftretens (tmax) und die Fläche unter der Kurve (AUC) von Acyclovir. Der Effekt der gleichen Chitosankonzentration wurde danach in einem Biozugänglichkeitmodell und in vier Permeationsmodellen untersucht. Auch wenn die Ergebnisse variabel waren, wurde in allen Permeationsmodellen bestätigt, dass Chitosan potentiell die intestinale Permeabilität beeinflussen kann. Ein Biowaiver auf der Basis des biopharmazeutischen Klassifikationssystems ist daher nicht gerechtfertigt bei einer Veränderung dieses Hilfsstoffes.Summary For orally administered products with systemic action, the plasma profile of the active pharmaceutical ingredient is generally considered as a measure of both efficacy and safety of the medicinal product. In case of changes to an existing product or development of a generic version, confirmation of equivalent plasma profiles is sought through a so-called bioequivalence study. Such an in vivo bioequivalence study in human volunteers may be waived if there is sufficient in vitro evidence of the equivalence of the test and reference products at issue. Biowaiver options depend on the characteristics of the API and the formulation. This thesis evaluates international (US, EU and WHO) regulatory conditions for biowaiving from a risk-based perspective with the aim to identify new biowaiver options. Regional differences in biowaiver conditions are obvious. Deviating definitions of the substance characteristic ‘solubility’ may have important consequences for the required evidence to show bioequivalence of a generic product. Harmonisation of the criteria as a common effort of authorities, academia and industry may facilitate application of the biowaiver approach and thus reduce the number of human studies. Understanding of the biopharmaceutic effects of excipients may extend biowaiver options. Lactose, for example, is used in highly variable quantities in similar tablets and capsules in combination with APIs from different BCS classes. In addition, an effect of lactose on other parameters than dissolution is not known from literature. Therefore, a comparative in vitro dissolution study is considered sufficient to support a change in lactose content if varied within the approved range. The biopharmaceutic effects of potential excipient chitosan on the absorption of acyclovir were explored both in humans and in several models. In a human study, chitosan showed a significant negative effect on Cmax, Tmax and AUC of acyclovir. The effect of the same chitosan on acyclovir was then tested in a bioaccessibility model as well as in four permeation models. The results showed potential intestinal permeability modulating characteristics of chitosan. A BCS-based biowaiver for a change in this potential excipient does thus not seem a viable option. Further studies are necessary to determine the suitability of the models for application as a tool for biowaiver purposes.119 Blätte