Highlight on the benefits of PBPK modeling: A link between drug properties and its in vivo performance

Physiologically based pharmacokinetic (PBPK) modeling or more recently also known as physiologically based biopharmaceutics modeling (PBBM) is a computer-aided (in silico) biopharmaceutical tool, designed to mechanistically describe bioperformance of a drug and predict its absorption and systemic availability. PBPK/PBBM was quickly adopted by pharmaceutical companies and medical regulatory agencies, its scope has expanded over the years, and nowadays PBPK/PBBM represents an essential tool in various phases of drug and formulation development (1). A major advantage of PBPK modeling over traditional in vitro and preclinical animal studies is the ability to link the physicochemical properties of a drug to its dissolution, absorption and disposition in a target patient or population, taking into account specific physiological conditions. This is accomplished through linked differential equations that describe simulta-neous or sequential dynamic processes that a drug undergoes in the body following dif-ferent routes of administration. PBPK predictions can refer to various physiological or disea-se states, so this unique approach can support personalized pharmacotherapy and drug/do-se/dosing regimen selection in different patient populations or individual patients (2). Although PBPK modeling can rely solely on the in silico generated data regarding drug’s properties (i.e., predicted based on the chemical structure of a drug), the prediction accuracy can be significantly improved with experimentally obtained input values. Therefore, any improvement in experimental drug characterization methods will inevitably lead to more reliable PBPK predictions. To illustrate the concept and implementation of PBPK modeling, this presentation will provide basic information on the structure of a PBPK model, and emphasis will be placed on case studies describing the interplay between drug-specific and physiologically relevant parameters that determine drug performance in vivo. Selected examples will be used to demonstrate how PBPK predictions can be used in conjunction with in vitro data on drug properties to answer clinically relevant questions, such as selecting appropriate drug therapy in bariatric patients, and assessing the impact of changes in gastric pH resulting from impaired gastric secretion or co-administration of proton pump inhibitors on drug dissolution, potential gastrointestinal precipitation and concomitant oral absorption.10th IAPC Meeting, Book of Abstract

Tackling the challenges of pharmacotherapy in gastric bypass patients: prediction of oral drug absorption

Poslednjih godina gojaznost postaje sve veći zdravstveni problem i za pacijente sa morbidnom gojaznošću operacija želuca, odnosno, gastrični bajpas može da predstavlja najbolje rešenje (1). Međutim, određene bolesti ili stanja koja prate gojaznost ostaju i nakon operacije, što za pacijente podrazumeva kontinuiranu farmakoterapiju. U ovakvim slučajevima posebnu pažnju treba obratiti na terapiju oralnim lekovima, jer kod barijatrijskih pacijenata često postoji potreba za podešavanjem vrste, doze, režima doziranja i/ili farmaceutskog oblika leka (2,3). Naime, izmenjeni fiziološki uslovi nakon operacije mogu značajno da utiču na brzinu rastvaranja i apsorpciju oralno primenjenih lekova, u zavisnosti od osobina lekovite supstance i tipa hirurške procedure. Dodatno, trenutne preporuke za oralnu primenu lekova barijatrijskim pacijentima, kao što su usitnjavanje tableta ili otvaranje kapsula (kada je dozvoljeno), uglavnom ne mogu da prevaziđu probleme vezane za lošu apsorpciju lekova, što dovodi do neuspeha terapije. Alternativni pristup u rešavanju ovakvih izazova predstavlja fiziološki zasnovano biofarmaceutsko modelovanje (PBBM), kompjuterski podržana metoda koja dovodi u vezu karakteristike lekovite supstance i farmaceutskog oblika leka sa specifičnim fiziološkim uslovima, te omogućava predviđanje bioperformansi leka kod određenog pacijenta ili u ciljanoj populaciji pacijenata. U ovom izlaganju će biti ilustrovani koncept i primena PBBM modelovanja za specifičnu populaciju pacijenata, sa fokusom na primere koji opisuju odnos između lek-specifičnih i fizioloških parametara koji utiču na ponašanje leka u organizmu. Izabrani primeri pokazuju kako PBBM predviđanja, u kombinaciji sa in vitro određenim karakteristikama lekovite supstance, mogu da se koriste za dobijanje odgovora na klinički značajna pitanja, poput odabira odgovarajuće terapije za barijatrijske pacijente (4,5).The prevalence of obesity has increased in recent years, and gastric bypass (bariatric) surgery may be the best treatment option for patients with severe (morbid) obesity (1). Yet, bariatric patients often suffer from concomitant diseases that require pharmacological treatment. In this context, special attention should be paid to oral drug dosing, as bariatric patients may need adjusted pharmacotherapy in terms of drug, dose/dosing regimen and/or dosage form selection (2,3). Namely, altered physiological conditions after bariatric surgery can markedly affect dissolution and absorption of orally administered drugs, depending on drug properties and the type of bariatric procedure. In addition, currently suggested approaches for oral drug administration in bariatric patients, such as crushing tablets or opening capsules (when permitted), generally fail to address the issues related to poor drug absorption, resulting in therapeutic failures. An alternative to tackle these challenges is physiologically based biopharmaceutical modeling (PBBM), a computer-based tool that relates drug and dosage form properties to specific physiological conditions, thus allowing prediction of drug bioperformance in a target patient or population group. This presentation will illustrate the concept and implementation of PBBM modeling for special patient population, focusing on the examples describing the interplay between drug-specific and physiologically relevant parameters that determine drug performance in vivo. The selected examples will demonstrate how PBBM predictions can be used in conjunction with in vitro data on drug properties to answer clinically relevant questions, such as selecting appropriate drug therapy in bariatric patients (4,5).Treći naučni simpozijum Saveza farmaceutskih udruženja Srbije sa međunarodnim učešćem „Lekovi za specifične populacije pacijenata: inovacijama ka unapređenju zdravstvenih ishoda“, Niš, Srbija, 26. oktobar 2023

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

Primena fiziološki zasnovanog modelovanja u razvoju inovativnih lekova: digitalni prozor u putovanje leka kroz organizam

The application of computer-based (in silico) modeling&simulation tools has become a global trend in different areas of science, including pharmaceutical sciences. These methods have been increasingly used in different phases of formulation development, starting with defining a sound formulation strategy, through the selection of drug dose and optimal formulation for clinical studies, to the prediction of drug absorption/disposition in different populations, identification of potential drug-drug interactions, prediction of bioequivalence study outcomes and justification of biowaivers (1). In silico tools for the prediction of drug bioperformance incorporate the so called physiologically-based models i.e., systems of data on physiological conditions and processes a drug undergoes in the organism, with an adequate mathematical background to describe these processes. As such, these models allow prediction of the expected therapeutic outcomes following drug administration, and offer a distinctive opportunity to test hypotheses and identify the underlying mechanisms responsible for the phenomena a drug undergoes in vivo. In other words, they act as a digital window to “drug’s journey through the body”. Physiologically-based models have been upgraded continuously, and relatively simple models evolved into the model-based drug development platforms, initiating a transformational change in drug formulation research&development. Opposed to the traditional “trial&error” methods, the outcomes of in silico modeling are based on the knowledge of in vivo processes, and planning of the optimal formulation strategy depending on drug biopharmaceutical properties and physiological characteristics of the target population. The selected examples will demonstrate the basic principles of in silico modeling in the development of pharmaceutical formulations.Primena računarski podržanih (in silico) metoda modelovanja i simulacija postala je globalni trend u različitim oblastima nauke, uključujući i farmaceutske nauke. Poslednjih godina ove metode nalaze sve širu primenu u različitim fazama razvoja leka, od definisanja strategije za razvoj formulacije, preko izbora odgovarajuće doze leka i optimalne formulacije za kliničke studije, do predviđanja apsorpcije i dispozicije leka u različitim populacijama pacijenta, identifikacije potencijalnih lek-lek interakcija, predviđanja ishoda studija biološke ekvivalencije i argumentovanja biowaiver-a (1). Programi za in silico simulaciju/predviđanje “ponašanja leka u organizmu” predstavljaju tzv. fiziološki-zasnovane modele, bazirane na saznanjima o fiziološkim uslovima i procesima kojima lek podleže u organizmu, kao i primeni odgovarajućih matematičkih relacija kojima je ove procese moguće opisati. Stoga predstavljaju korisno sredstvo, ne samo za predviđanje očekivanih terapijskih ishoda koji prate primenu leka, već i za testiranje hipoteza, odnosno, identifikaciju mehanizama koji su odgovorni za fenomene kojima lek podleže in vivo. Drugim rečima, predstavljaju digitalni prozor u “putovanje leka kroz organizam”. Fiziološki-zasnovani modeli se kontinuirano unapređuju, te su relativno jednostavni modeli evolirali u tzv. model-zasnovane platforme za razvoj lekova, što je na neki način pokrenulo revoluciju u oblasti istraživanja i razvoja lekova. Za razliku od tradicionalnih metoda „pokušaja i greške“, ishodi in silico modelovanja su zasnovani na poznavanju procesa koji se dešavaju in vivo i planiranju optimalne strategije za razvoj formulacije, u zavisnosti od biofarmaceutskih svojstava lekovite supstance i fizioloških karakteristika ciljane populacije pacijenata. U ovom izlaganju će, na odabranim primerima, biti prikazani osnovni principi in silico modelovanja u razvoju formulacija farmaceutskih preparata.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Model-Informed Drug Development: In Silico Assessment of Drug Bioperformance following Oral and Percutaneous Administration

The pharmaceutical industry has faced significant changes in recent years, primarily influenced by regulatory standards, market competition, and the need to accelerate drug development. Model-informed drug development (MIDD) leverages quantitative computational models to facilitate decision-making processes. This approach sheds light on the complex interplay between the influence of a drug’s performance and the resulting clinical outcomes. This comprehensive review aims to explain the mechanisms that control the dissolution and/or release of drugs and their subsequent permeation through biological membranes. Furthermore, the importance of simulating these processes through a variety of in silico models is emphasized. Advanced compartmental absorption models provide an analytical framework to understand the kinetics of transit, dissolution, and absorption associated with orally administered drugs. In contrast, for topical and transdermal drug delivery systems, the prediction of drug permeation is predominantly based on quantitative structure–permeation relationships and molecular dynamics simulations. This review describes a variety of modeling strategies, ranging from mechanistic to empirical equations, and highlights the growing importance of state-of-the-art tools such as artificial intelligence, as well as advanced imaging and spectroscopic techniques

Savremeni farmaceutski oblici nesteroidnih antiinflamatornih lekova

Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased risk of serious gastrointestinal side effects. Therefore, recent trends in the development of NSAIDs aim to reduce the incidence of side effects, and improve patient compliance. One of the strategies to improve efficacy and safety of oral NSAIDs is the development of combination products that contain gastroprotective agents. Several products containing NSAID in combination with proton pump inhibitors (ketoprofen/omeprazole, naproxen/esomeprazole), H2-receptor antagonists (ibuprofen/famotidine), and prostaglandin analogues (diclofenac/misoprostol) are currently available on the market. Another approach refer to the special formulation design to allow dose reduction while preserving drug therapeutic efficacy. An example is SoluMatrix® technology, a manufacturing process that produce submicron-sized drug particles with enhanced dissolution and absorption properties. Patented SoluMatrix® technology has been successfully employed to develop low-dose diclofenac, meloxicam, indomethacin and naproxen products. Topical NSAID formulations enable drug delivery to target tissues, while reducing systemic exposure and concomitant side effects associated with oral NSAIDs. Dermal/transdermal NSAID delivery systems are subject of intensive investigation. So far, several 'advanced' drug delivery systems with diclofenac, ibuprofen and ketoprofen have been designed.Hronična primena oralnih nesteroidnih antiinflamatornih lekova (NSAIL) praćena je povećanim rizikom za nastanak ozbiljnih gastrointestinalnih neželjenih dejstava. Da bi se smanjila mogućnost nastanka ovih neželjenih dejstava i poboljšala prihvatljivost od strane pacijenata, primenjeni su novi pristupi u razvoju formulacija NSAIL. Jedan od pristupa unapređenju efikasnosti i bezbednosti NSAIL za oralnu primenu podrazumeva razvoj kombinovanih preparata koji sadrže odgovarajuću supstancu sa gastroprotektivnim dejstvom. Komercijalno su dostupni preparati NSAIL u kombinaciji sa inhibitorima protonske pumpe (ketoprofen/omeprazol, naproksen/esomeprazol), antagonistima H2 receptora (ibuprofen/famotidin) i analozima prostaglandina (diklofenak/mizoprostol). Drugi pristup podrazumeva primenu odgovarajućih farmaceutsko-tehnoloških postupaka kojima se obezbeđuje ispoljavanje željenog terapijskog dejstva uz primenu manje doze leka. Ovo je postignuto primenom takozvane SoluMatrix® tehnologije koja je zasnovana na primeni čestica submikronskih veličina, čime je omogućeno znatno brže rastvaranje i apsorpcija lekovite supstance nakon oralne primene. Patentirana SoluMatrix® tehnologija je uspešno primenjena za razvoj preparata sa diklofenakom, meloksikamom, indometacinom i naproksenom. Dermalna primena NSAIL omogućava permeaciju aktivne supstance na mesto delovanja, uz izostanak potencijalnih neželjenih dejstava koji su povezani sa oralnom primenom lekova. Terapijski sistemi za dermalnu/transdermalnu primenu NSAIL su predmet intenzivnih istraživanja. Za sada su razvijene 'napredne' formulacije sa diklofenakom, ibuprofenom i ketoprofenom

Bcs class iv oral drugs and absorption windows: Regional-dependent intestinal permeability of furosemide

Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. In addition, advanced in-silico simulations (GastroPlus®) were used to elucidate furosemide regional-dependent absorption pattern. Metoprolol was used as the low/high permeability class boundary. Furosemide was found to be a low-solubility compound. Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Similarly, segmental-dependent in-vivo intestinal permeability was revealed; as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. The opposite trend was evident for metoprolol. Theoretical physicochemical analysis based on ionization, pKa, and partitioning predicted the same trend and confirmed the experimental results. Computational simulations clearly showed the effect of furosemide’s regional-dependent permeability on its absorption, as well as the critical role of the drug’s absorption window on the overall bioavailability. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products

In silico predviđanje apsorpcije karbamazepina nakon oralne primene tableta sa trenutnim oslobađanjem

The main prerequisite to establish quantitative in vitro-in vivo correlation (IVIVC) and define biorelevant in vitro methodology is to identify drug dissolution profile in vivo. When intravenous data are not available due to poor drug solubility, oral drug absorption cannot be estimated by means of conventional pharmacokinetic analysis. Development of the mechanistic absorption models has therefore received widespread attention over the past few years. The objective of this study is to: I) develop drug-specific absorption model for carbamazepine using in silico absorption model, II) use the generated absorption model to provide the target in vivo dissolution profile for IVIVC, III) identify biorelevant dissolution specifications for carbamazepine immediate-release tablets, and IV) compare the obtained results with the results of the previous studies. GastroPlusTM software package was used for computer simulations. The required input parameters were experimentally determined, in silico predicted and/or taken from the literature. Convolution approach was applied to assess the relationship between the in vitro and in vivo data. The presented data demonstrated that in silico simulation technology can be successfully used to predict carbamazepine absorption profile, and that the generated plasma concentration profile can serve as the target profile for IVIVC and identification of biorelevant dissolution specifications for carbamazepine immediate-release tablets.Da bi se procenila mogućnost primene laboratorijskih (in vitro) i računarskih (in silico) metoda za predviđanje apsorpcije lekovite supstance u gastrointestinalnom traktu (GIT-u) i uspostavljanje in vitro-in vivo korelacije (IVIVK), neophodno je prethodno identifikovati in vivo profil oslobađanja lekovite supstance iz preparata. U slučaju lekovitih supstanci koje, zbog slabe rastvorljivosti, nije moguće primeniti intravenski, apsorpciju nije moguće predvideti primenom konvencionalnih farmakokinetičkih metoda, pa je zato poslednjih godina veliki istraživački interes usmeren ka primeni mehanističkih apsorpcionih modela. Cilj ovog rada je da se: i) primenom in silico apsorpcionog modela razvije lek-specifičan model za predviđanje apsorpcije karbamazepina, ii) identifikuje profil in vivo oslobađanja koji će služiti kao osnova za uspostavljanje IVIVK, iii) identifikuju biorelevantne specifikacije za brzinu rastvaranja karbamazepina iz tableta sa trenutnim oslobađanjem i iv) dobijeni rezultati uporede sa rezultatima prethodnih studija. Za in silico predviđanje apsorpcije karbamazepina primenjen je GastroPlusTM programski paket. Vrednosti ulaznih parametara potrebnih za simulaciju su preuzete iz literature ili su korišćene in silico predviđene i/ili eksperimentalno određene vrednosti. Za utvrđivanje stepena korelacije između in vitro i in vivo podataka primenjen je konvolucioni pristup uspostavljanju IVIVK. Dobijeni rezultati su pokazali da je primenom in silico metode moguće uspešno simulirati apsorpciju karbamazepina nakon oralne primene i da se dobijeni profil koncentracije leka u krvi može koristiti kao ciljni profil za IVIVK i identifikovanje 'biorelevantnih' specifikacija za in vitro brzinu rastvaranja karbamazepina iz tableta

Savremeni trendovi u formulaciji i primeni lekova u terapiji depresije kod dece i odraslih

Depression is the most common mental disorder in the general population and often requires long-term administration of antidepressants. Development of the modified release antidepressant products has led to the lower incidence of the adverse effects and improvement in the adherence, and subsequently to better therapeutic outcomes. Modified release may involve delayed and/or prolonged release of antidepressants. There is an increasing number of marketed antidepressant products in the form of orally dispersible tablets, for the treatment of a particular group of patients with impaired swallowing. Pharmacotherapy of depression in children represents a great challenge due to insufficient data regarding efficacy and safety. Furthermore, in the market of Republic of Serbia, there are no antidepressant products in the age-appropriate dosage forms for pediatric patients. It is, therefore, of great importance to address the risks related to the application of the conventional dosage forms of marketed antidepressants (tablets, hard capsules) to children. Novel treatment options include development of carriers for targeted delivery of antidepressants in the central nervous system. Intranasal administration of antidepressants is particularly favored since it allows the delivery of active ingredients via olfactory and trigeminal nerves. Other transmucosal routes of administration, such as buccal or sublingual, can provide improved therapeutic outcomes, compared to the conventional oral administration, due to circumvention of the intense metabolism of the active ingredients and undesired gastrointestinal side effects.Depresija je najčešći mentalni poremećaj u opštoj populaciji i neretko zahteva dugotrajnu primenu lekova iz grupe antidepresiva. Razvojem preparata sa modifikovanim oslobađanjem lekovite supstance omogućeno je smanjenje neželjenih efekata i poboljšanje adherence, a samim tim i poboljšanje terapijskih ishoda. Modifikacija oslobađanja podrazumeva odloženo i/ili produženo oslobađanje antidepresiva. Za terapiju određene grupe pacijenata sa otežanim gutanjem od velikog značaja je i sve veći broj registrovanih preparata u obliku oralno-disperzibilnih tableta. Farmakoterapija depresije kod dece predstavlja veliki izazov zbog nedostatka podataka o efikasnosti i bezbednosti. Takođe, na tržištu Republike Srbije nisu registrovani preparati sa antidepresivima u farmaceutskim oblicima prilagođenim pedijatrijskom uzrastu. Zbog toga je veoma značajno razmotriti rizike povezane sa primenom konvencionalnih farmaceutskih oblika antidepresiva (tablete, tvrde kapsule) kod dece. Savremeni farmaceutski oblici podrazumevaju razvoj nosača za ciljanu isporuku antidepresiva u centralni nervni sistem. Naročito se ističe intranazalni put primene jer omogućava isporuku lekovitih supstanci putem olfaktornog i trigeminalnog nerva. I drugi transmukozni putevi primene, poput bukalnog ili sublingvalnog, omogućavaju unapređenje terapijskih ishoda jer se, u odnosu na peroralni put primene, zaobilazi intenzivan metabolizam lekovitih supstanci i izbegavaju neželjeni gastrointestinalni efekti