Development of an ion-pair to improve the colon permeability of a low permeability drug: Atenolol.
Abstract To ensure the optimal performance of oral controlled release formulations, drug colon permeability is one of the critical parameters. Consequently developing this kind of formulations for low permeability molecules requires strategies to increase their ability to cross the colonic membrane. The objective of this work is to show if an ion-pair formation can improve the colon permeability of atenolol as a low permeability drug model. Two counter ions have been tested: brilliant blue and bromophenol blue. The Distribution coefficients at pH 7.00 (DpH7) of atenolol, atenolol + brilliant blue and atenolol + bromophenol blue were experimentally determined in n-octanol. Moreover, the colo…
Erratum: Mangas-Sanjuán, V.; et al. Assessment of the Inter-Batch Variability of Microstructure Parameters in Topical Semisolids and Impact on the Demonstration of Equivalence. Pharmaceutics 2019, 11, 503
Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µg/0.5 mg/g) in order to define the acceptance range that allows concluding equivalence between these batches. Being batches of the same reference product, they are expected to be clinically equivalent and possess similar microstructure. The 90% confidence intervals for the test/reference ratio of these physical parameters …
In vitro–in vivocorrelations: general concepts, methodologies and regulatory applications
The major objective of in vitro-in vivo correlations is to be able to use in vitro data to predict in vivo performance serving as a surrogate for an in vivo bioavailability test and to support biowaivers. Therefore, the aims of this review are: (i) to clarify the factors involved during bio-predictive dissolution method development; and (ii) the elements that may affect the mathematical analysis in order to exploit all information available. This article covers the basic aspects of dissolution media and apparatus used in the development of in vivo predictive dissolution methods, including the latest proposals in this field as well as the summary of the mathematical methods for establishing …
Development of antibiotic loaded biodegradable matrices to prevent superficial infections associated to total knee arthroplasty.
Abstract Development of a pharmaceutical form for the superficial infections related with arthroplasties would be helpful for clinical practice. In this context, we set out to evaluate ciprofloxacin and gentamicin elution from systems based on chitosan. Films and semisolid hydrogels containing chitosan alone (2%) or in combination with gelatin (6%) or different proportions (from 12% to 36%) of tetrakis-(hydroxymethyl)-phosphonium-chloride (THPC) were tested as delivery systems. Different antibiotic doses were assayed (0.5 mg/cm2,1 mg/cm2 and 2 mg/cm2). Antibiotic release was studied for each formulation. In vitro cytocompatibility studies and a simulation exercise for bioactivity evaluation…
Impact of nutritional status on the oral bioavailability of leucine administered to rats as part of a standard enteral diet.
Summary Background To investigate the absorption and relative bioavailability of leucine administered orally as part of an enteral diet in well and malnourished animals. Methods Two groups – RN (regular nutrition) and PCR (protein-calorie restricted) – were fed with different diets for 23–25 days. Rats from each group were assigned randomly to one of three treatments (water, T-Diet Plus Standard ® (problem) or Isosource ST ® (reference)) administered in single ( N = 76) or multiple ( N = 39) doses. Blood samples were assayed for leucine content. Area under the curve (AUC) was calculated by non-compartmental analysis. Log-transformed AUC(s) were statistically compared by analysis of varian…
Relationship Between Glucocerebrosidase Activity and Clinical Response to Enzyme Replacement Therapy in Patients With Gaucher Disease Type I
The quantification of enzyme activity in the patient treated with enzyme replacement therapy (ERT) has been suggested as a tool for dosage individualization, so we conducted a study to evaluate the relationship between glucocerebrosidase activity and clinical response in patients with Gaucher disease type I (GD1) to ERT. The study included patients diagnosed with GD1, who were being treated with ERT, and healthy individuals. Markers based on glucocerebrosidase activity measurement in patients' leucocytes were studied: enzyme activity at 15 min. post-infusion (Act75 ) reflects the amount of enzyme that is distributed in the body post-ERT infusion, and accumulated glucocerebrosidase activity …
Relevance of Multidrug Resistance Proteins on the Clinical Efficacy of Cancer Therapy
Variations in drug uptake and efflux, as well as changes in intracellular drug entrapment and distribution may represent important resistance mechanisms to cancer therapy. A variety of ATP binding cassette transporters (ABC) localised in multiple cell membranes is implied in those phenomena, representing a mechanism of protection of cells against xenobiotics. Many cancer cell lines over express some ABC transporters, especially p-glycoprotein, MRP1 and BCRP. This over expression is related to worse cancer treatment outcome and, in some cases, reduced overall survival of cancer patients. This paper reviews the location and physiological role of the three transporters mentioned and also descr…
In vitro skin penetration of bronidox, bronopol and formaldehyde from cosmetics
The objective was to evaluate the influence of the formulation in the in vitro transdermal absorption through pig ear skin of three preservatives, bronopol, bronidox and formaldehyde as well as the absorption of formaldehyde from bronopol and dimethyloldimethyl hydantoin (DMDM hydantoin). An aqueous solution, an O/W emulsion and a hydrogel were assayed. Bronidox and bronopol absorption depends on the formulation. The O/W emulsion was the system that least promoted absorption of bronidox while the absorption of bronopol was lower from the hydrogel. The aqueous solution provided maximal transdermal absorption of both preservatives. Moreover, the transdermal absorption of formaldehyde released…
Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice
MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mo…
In Situ Perfusion Model in Rat Colon for Drug Absorption Studies: Comparison with Small Intestine and Caco-2 Cell Model.
Our aim is to develop and to validate the in situ closed loop perfusion method in rat colon and to compare with small intestine and Caco-2 cell models. Correlations with human oral fraction absorbed (Fa) and human colon fraction absorbed (Fa_colon) were developed to check the applicability of the rat colon model for controlled release (CR) drug screening. Sixteen model drugs were selected and their permeabilities assessed in rat small intestine and colon, and in Caco-2 monolayers. Correlations between colon/intestine/Caco-2 permeabilities versus human Fa and human Fa_colon have been explored to check model predictability and to apply a BCS approach in order to propose a cut off value for CR…
Current Evidence, Challenges, and Opportunities of Physiologically Based Pharmacokinetic Models of Atorvastatin for Decision Making
Atorvastatin (ATS) is the gold-standard treatment worldwide for the management of hypercholesterolemia and prevention of cardiovascular diseases associated with dyslipidemia. Physiologically based pharmacokinetic (PBPK) models have been positioned as a valuable tool for the characterization of complex pharmacokinetic (PK) processes and its extrapolation in special sub-groups of the population, leading to regulatory recognition. Several PBPK models of ATS have been published in the recent years, addressing different aspects of the PK properties of ATS. Therefore, the aims of this review are (i) to summarize the physicochemical and pharmacokinetic characteristics involved in the time-course o…
Enhancement of nortriptyline penetration through human epidermis: influence of chemical enhancers and iontophoresis.
Abstract Different known percutaneous chemical enhancers and iontophoresis have been tested in-vitro to study their ability to increase transdermal absorption of nortriptyline hydrochloride (20 mg mL−1). The chemicals 1-dodecanol, Span 20, Azone, (R)-(+)-limonene or isopropyl myristate were used as an overnight pretreatment at 5% (w/w) in ethanol. Furthermore, isopropyl myristate (20%, w/w) and propylene glycol (15%, w/w) were tested in the same vehicle. Iontophoresis was applied directly to the nortriptyline hydrochloride donor solution for three different concentrations (20, 2 and 0.5 mgmL−1). The chemical enhancers slightly increased the nortriptyline transdermal flux but iontophoresis w…
Usefulness of Caco-2/HT29-MTX and Caco-2/HT29-MTX/Raji B Coculture Models To Predict Intestinal and Colonic Permeability Compared to Caco-2 Monoculture
The Caco-2 cellular monolayer is a widely accepted in vitro model to predict human permeability but suffering from several and critical limitations. Therefore, some alternative cell cultures to mimic the human intestinal epithelium, as closely as possible, have been developed to achieve more physiological conditions, as the Caco-2/HT29-MTX coculture and the triple Caco-2/HT29-MTX/Raji B models. In this work the permeability of 12 model drugs of different Biopharmaceutical Classification System (BCS) characteristics, in the coculture and triple coculture models was assessed. Additionally, the utility of both models to classify compounds according to the BCS criteria was scrutinized. The obta…
Adsorption of methotrexate and calcium leucovorin onto cholestyramine in vitro.
Abstract Methotrexate (MTX), an antimetabolite of folic acid, is a drug widely used in the treatment of different types of cancer. When high doses are administered, it is necessary to interrupt its action by administering calcium leucovorin (CaL). The main pathway of MTX and CaL elimination in humans occurs through the kidney, but about 10% is excreted in the faeces via the bile. Drugs, foods and sorbents in intestinal lumen modify MTX and CaL reabsorption. Individual and simultaneous studies on the adsorption of MTX and CaL from aqueous phosphate buffer by cholestyramine were carried out in order to calculate the adsorption process of MTX and CaL to cholestyramine, and to characterize the …
Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats
The main objective of this study was to develop a pharmacokinetic model in order to describe the intestinal absorption of erlotinib in rat and to quantify the interaction of levofloxacin on this process in well- and under-nourished rats. Absorption studies were performed in male Wistar rats. Concentration-time profiles in proximal and distal intestine were analysed through non-linear mixed effect modelling using the NONMEM software version 7.3. Simulations were performed in order to explore the influence of covariates on the apparent absorption rate constant. A passive absorption and an active secretion process best-described erlotinib absorption from lumen to enterocyte. The developed mode…
Hydroxypropylmethylcellulose films for the ophthalmic delivery of diclofenac sodium
Abstract Objectives The aim of this study was to prepare diclofenac/hydroxypropylmethylcellulose (HPMC) and diclofenac-loaded nanoparticles/HPMC films as potential systems for ocular delivery. Methods Two different concentration of the polymer were used: 1.5 and 2.0% w/v. Chitosan–hyaluronic acid nanoparticles were prepared by the ionotropic gelation technique. Nanoparticles were characterized by transmission electron microscopy, dynamic light scattering, drug encapsulation efficiency and rheological studies. In-vitro drug studies and corneal penetration release studies were carried out. Drug release mechanism was finally evaluated by fitting the Ritger and Peppas equation to data. In addit…
Estimators and confidence intervals of f2 using bootstrap methodology for the comparison of dissolution profiles
Abstract Background and objectives: The most widely used method to compare dissolution profiles is the similarity factor f 2 . When this method is not applicable, the confidence interval of f 2 using bootstrap methodology has been recommended instead. As neither details of the estimator nor the types of confidence intervals are described in the guidelines, the suitability of five estimators and fourteen types of confidence intervals were investigated in this study by simulation. Methods: One million individual dissolution profiles were simulated for the reference and test populations with predefined target population f 2 values, where random samples of different sizes were drawn without rep…
Quality Improvement Project to Evaluate Discharge Prescriptions in Children With Cystic Fibrosis
Introduction: Cystic Fibrosis (CF) requires multiple pharmaceutical treatments, elevating the risk of medication errors (ME), which may compromise patient safety. This study aimed to improve the quality of discharge prescriptions (DPs) using indicators following admissions for IV antibiotics in pediatric CF patients. Methods: This project involved a longitudinal observational retrospective descriptive study followed by a longitudinal quasi-experimental prospective phase between January 2013 and December 2016 in CF patients admitted to a London Children's Hospital. The CF pharmacist reviewed DPs. Six rights of medication administration were defined (6R): dose, drug, frequency, duration of tr…
In-situ intestinal rat perfusions for human Fabs prediction and BCS permeability class determination: Investigation of the single-pass vs. the Doluisio experimental approaches.
Intestinal drug permeability has been recognized as a critical determinant of the fraction dose absorbed, with direct influence on bioavailability, bioequivalence and biowaiver. The purpose of this research was to compare intestinal permeability values obtained by two different intestinal rat perfusion methods: the single-pass intestinal perfusion (SPIP) model and the Doluisio (closed-loop) rat perfusion method. A list of 15 model drugs with different permeability characteristics (low, moderate, and high, as well as passively and actively absorbed) was constructed. We assessed the rat intestinal permeability of these 15 model drugs in both SPIP and the Doluisio methods, and evaluated the co…
A Bayesian Method for Predicting 5‐Fluorouracil Pharmacokinetic Parameters Following Short‐Term Infusion in Patients With Colorectal Cancer
Abstract The objective of this study was to develop a population pharmacokinetic model and validate it using a Bayesian approach for predicting, a priori and a posteriori , the individual volume of distribution ( V d ) and clearance ( Cl ) of 5‐fluorouracil (5‐FU) given as short‐term intravenous infusion in weekly and multiple doses. Forty‐four patients were divided in group A (5‐FU weekly doses) including 27 patients with nonmetastatic colorectal adenocarcinoma treated with 450 mg/m 2 of 5‐FU, 1 day per week for 48 doses, plus oral levamisol (50 mg/8 h) for 3 days, every 15 days and group B (5‐FU multiple doses) including 17 patients with metastatic colorectal adenocarcinoma, receiving 5‐F…
Physico-Chemical Stability of Admixtures of Vinflunine Used in Clinical Practice.
Procedure of administration of vinflunine is complex and consists of an Y-site injection with fluid at different speeds. Dose is diluted with 100 mL of 0.9% sodium chloride or 5% glucose and infused with half of the 500 mL bag of the fluid over 20 min; after that, the remaining fluid is administered at 300 mL/h. In this study, chemical stability and physical compatibility of vinflunine diluted with in 500 mL of both fluids were evaluated to simplify the administration procedure (infusion of mixture on 20 min followed by 250 mL of fluid at 300 mL/h). Physical compatibility and chemical stability were evaluated at two temperatures and protected from and exposed to light. Physical compatibilit…
Multi-output Model with Box-Jenkins Operators of Quadratic Indices for Prediction of Malaria and Cancer Inhibitors Targeting Ubiquitin- Proteasome Pathway (UPP) Proteins.
The ubiquitin-proteasome pathway (UPP) is the primary degradation system of short-lived regulatory proteins. Cellular processes such as the cell cycle, signal transduction, gene expression, DNA repair and apoptosis are regulated by this UPP and dysfunctions in this system have important implications in the development of cancer, neurodegenerative, cardiac and other human pathologies. UPP seems also to be very important in the function of eukaryote cells of the human parasites like Plasmodium falciparum, the causal agent of the neglected disease Malaria. Hence, the UPP could be considered as an attractive target for the development of compounds with Anti-Malarial or Anti-cancer properties. R…
PLGA nanoparticles are effective to control the colonic release and absorption on ibuprofen.
The oral controlled release (CR) formulations have become more important in recent years. Among them, the polymeric nanoparticles have been thoroughly studied during the last decades, consequently they are extensively employed for a broad range of applications and drugs. The objective of this research was to develop polymeric nanoparticles (NPs) of ibuprofen with poly(lactic-co-glycolic) acid (PLGA) as polymer, and to test their applicability for oral CR formulations development. Different proportions of drug/polymer were employed to develop the ibuprofen NPs and their in vitro release profiles were analysed. The in situ segmental permeability of ibuprofen was tested in Wistar rat and demon…
Use of nonlinear mixed effect modeling for the intestinal absorption data: application to ritonavir in the rat.
The aim of this study is to investigate in situ the mechanisms involved in the gastrointestinal absorption of ritonavir in the rat, as an animal model for preclinical studies of anti-HIV agents in vivo. Four ritonavir solutions (40, 27, 13 and 7 microM) in the presence of 1% dimethylsulfoxide (DMSO) were perfused in the small intestine of anaesthetised rats. Effects of DMSO on the intestinal permeability were investigated using solutions containing antipyrine 1.33 mM and ritonavir 7 microM with and without 1% of DMSO. Antipyrine and ritonavir transport was not modified in the presence of 1% of DMSO. The population pharmacokinetic parameters of the ritonavir intestinal transport were obtaine…
Assessment of the Inter-Batch Variability of Microstructure Parameters in Topical Semisolids and Impact on the Demonstration of Equivalence
Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µ
Influence of Inter- and Intra-Batch Variability on the Sample Size Required for Demonstration of Equivalent Microstructure of Semisolid Dosage Forms
Inter- and intra-batch variability of the quality attributes contribute to the uncertainty for demonstrating equivalent microstructure of post-approval changes and generic/hybrids of semisolid topical products. Selecting a representative sample size to describe accurately the in vitro properties of semisolids and to reach enough statistical power to demonstrate similarity between two semisolid topical products is currently challenging. The objective of this work is to establish the number of batches and units per batch to be compared based on different inter-batch and intra-batch variability to demonstrate equivalence in the physical characteristics of the products that ensure a similar mic…
In Situ Study of the Effect of Naringin, Talinolol and Protein-Energy Undernutrition on Intestinal Absorption of Saquinavir in Rats
To study the potential interactions of naringin (NAR), talinolol (TAL) and protein-energy undernutrition (PEU) in the absorption process of saquinavir (SQV), perfusion experiments were performed in the small intestine of rats at different SQV concentrations. The results obtained demonstrated that SQV intestinal absorption was described by simultaneous passive diffusion (kdif = 3.44 hr) and saturable absorption (Vma = 127.31 lM ⁄ hr; Kma =1 0.50lM) together with a capacity-limited efflux (Vms = 270.53 lM ⁄ hr; Kms =2 3.44lM). The competitive inhibition constants of NAR on the SQV input and efflux processes were (IC50)a =3 .98l Ma nd(IC50)s = 5.00 lM, respectively. NAR significantly decreased…
Enzyme-responsive silica mesoporous supports capped with azopyridinium salts for controlled delivery applications
11 páginas, 7 figuras, 3 tablas y 2 esquemas
Applicability of the STOPP/START criteria to older polypathological patients in a long-term care hospital
Objectives To analyse the applicability of the STOPP/START criteria as a tool to identify patients with potentially inappropriate medications (PIM) during pharmaceutical validation of prescriptions in a long-term care hospital, to identify risk factors for PIM and to characterise the physiological systems and drugs more frequently associated with these PIM. Methods An interventional, prospective and longitudinal study was conducted in polypathological patients aged >65 years. Usual pharmaceutical care and the STOPP/START criteria were used to identify PIM and to plan pharmaceutical interventions at admission. At discharge, the discharge summaries were reviewed using the STOPP/START criteria…
Defining level A IVIVC dissolution specifications based on individual in vitro dissolution profiles of a controlled release formulation.
Regulatory guidelines recommend that, when a level A IVIVC is established, dissolution specification should be established using averaged data and the maximum difference between AUC and Cmax between the reference and test formulations cannot be greater than 20%. However, averaging data assumes a loss of information and may reflect a bias in the results. The objective of the current work is to present a new approach to establish dissolution specifications using a new methodology (individual approach) instead of average data (classical approach). Different scenarios were established based on the relationship between in vitro-in vivo dissolution rate coefficient using a level A IVIVC of a cont…
Bioavailability and pharmacokinetic model for ritonavir in the rat.
The aim of this study is to investigate in vivo the oral bioavailability of ritonavir and to evaluate the pharmacokinetic model that best describes the plasma concentration behavior after oral and intravenous administration. Male Wistar rats were intravenously administered at 3 mg dose of pure ritonavir and oral administered at 4.6 +/- 2.5 mg of diluted Norvir. Blood samples were taken by means of the jugular vein for a 24 h period of time. An analytical high-performance liquid chromatography (HPLC) technique was developed in order to quantify ritonavir plasma concentrations. A nonlinear modeling approach was used to estimate the pharmacokinetic parameters of interest. Results showed that a…
Population modelling to describe pharmacokinetics of amiodarone in rats: Relevance of plasma protein and tissue depot binding
The objective of this paper was to characterize the disposition phase of AM in rats, after different high doses and modalities of i.v. administration. Three fitting programs, WINNONLIN, ADAPT II and NONMEM were employed. The two-stage fitting methods led to different results, none of which can adequately explain amiodarone's behaviour, although a great amount of data per subject is available. The non-linear mixed effect modelling approach allows satisfactory estimation of population pharmacokinetic parameters, and their respective variability. The best model to define the AM pharmacokinetic profile is a two-compartment model, with saturable and dynamic plasma protein binding and linear tiss…
N-Succinyl-chitosan systems for 5-aminosalicylic acid colon delivery: In vivo study with TNBS-induced colitis model in rats
5-Aminosalicylic acid (5-ASA) loaded N-Succinyl-chitosan (SucCH) microparticle and freeze-dried system were prepared as potential delivery systems to the colon. Physicochemical characterization and in vitro release and swelling studies were previously assessed and showed that the two formulations appeared to be good candidates to deliver the drug to the colon. In this work the effectiveness of these two systems in the treatment of inflammatory bowel disease was evaluated. In vitro mucoadhesive studies showed excellent mucoadhesive properties of both the systems to the inflamed colonic mucosa. Experimental colitis was induced by rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNB…
Segmental-dependent permeability throughout the small intestine following oral drug administration: Single-pass vs. Doluisio approach to in-situ rat perfusion
Abstract Intestinal drug permeability is position dependent and pertains to a specific point along the intestinal membrane, and the resulted segmental-dependent permeability phenomenon has been recognized as a critical factor in the overall absorption of drug following oral administration. The aim of this research was to compare segmental-dependent permeability data obtained from two different rat intestinal perfusion approaches: the single-pass intestinal perfusion (SPIP) model and the closed-loop (Doluisio) rat perfusion method. The rat intestinal permeability of 12 model drugs with different permeability characteristics (low, moderate, and high, as well as passively and actively absorbed…
A model-based meta-analysis of sofosbuvir-based treatments in chronic hepatitis C patients.
The objective of this study was to compare the efficacy of sofosbuvir-based treatments in patients with chronic hepatitis C virus (HCV) infection using a model-based meta-analysis (MBMA). A bibliographic search was performed to identify clinical trials involving sofosbuvir as a unique direct-acting antiviral (DAA) agent or together with daclatasvir, ledipasvir or simeprevir for the treatment of diagnosed HCV infection. The time course of the virological response (VR) was modelled to estimate the effect of treatment and the influence of population characteristics on the longitudinal efficacy profile. The model was validated and simulations of 10 different treatment schedules were performed. …
Relationship between rheological properties, in vitro release and in vivo equivalency of topical formulations of diclofenac.
Determination of bioequivalence remains a challenge in generic topical drug development. To support pharmacokinetic studies, strategies to demonstrate microstructure sameness of the products being compared include in vitro evaluations, such as the comparison of rheological properties, droplet size and in vitro release rates. Nevertheless, defining the appropriate acceptance range to consider equivalence between test and reference formulation is complex. To shed more light into this issue, in vitro release and rheological properties were compared to in vivo bioequivalence data (systemic blood measurements within a clinical trial) after topical application of a single dose. Test and reference…
Impact of nutritional status on the pharmacokinetics of erlotinib in rats
Malnourishment is a complex condition in which physiopathological changes take place in multiple systems as a result of energy, protein and nutrient deficiency. The purpose of this study was to evaluate, using an experimental animal model, the impact of nutritional status on the pharmacokinetic profile of erlotinib, a reversible, highly selective, human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Two groups of rats -WN (well-nourished) and UN (undernourished) - were fed with different diets for 23-26 days. Rats were assigned randomly to one of three erlotinib treatments (n = 42) consisting of a single dose administered intravenously (i.v.), via oral solution or v…
A preclinical study to model taurine pharmokinetics in the undernourished rat
AbstractMalnutrition is a common feature of chronic and acute diseases, often associated with a poor prognosis, including worsening of clinical outcome, owing, among other factors, to dysfunction of the most internal organs and systems affecting the absorption, metabolism and elimination of drugs and nutrients. Taurine is involved in numerous biological processes and is required in increased amounts in response to pathological conditions. The aim of this study was to describe the behaviour of taurine in well-nourished (WN) rats and to analyse the influence of protein–energy undernutrition on the pharmacokinetic (PK) parameters of taurine, using a PK model. Wistar rats were randomly distribu…
A multilevel object-oriented modelling methodology for physiologically-based pharmacokinetics (PBPK): Evaluation with a semi-mechanistic pharmacokinetic model.
Abstract Background and objective The aims of this study are (i) to assess the predictive reliability of the physiologically based software PhysPK versus the well-known population approach software NONMEM for the cited semi-mechanistic PK model, (ii) to determine whether these modelling approaches are interchangeable and (iii) to compare acausal with causal modelling approaches in the framework of semi-mechanistic PK models. Methods A semi-mechanistic model was proposed, which assumed oral administration of a solid dosage form with a peripheral compartment and two active metabolites. The model incorporates intestinal transit, dissolution limited by solubility, variable efflux transporter ex…
Comparison of segmental-dependent permeability in human and in situ perfusion model in rat.
Abstract Nowadays, alternative methods have been developed to predict intestinal permeability values in human as in vitro, in situ or ex vivo methods. They were developed by the necessity to avoid the problems of the human permeability experiments. However, determination of human permeability is needed to properly validate the alternative methods. For this reason, recently, Dahlgren et al. published an indirect method based on a deconvolution technique to estimate the human permeability in different gastrointestinal segments (jejunum, ileum and colon). Therefore, the objective of this research was to demonstrate that Doluisio technique is a useful method to predict the human permeability in…
Design, characterization and in vitro evaluation of 5-aminosalicylic acid loaded N-succinyl-chitosan microparticles for colon specific delivery
The objective of this study was to prepare NS-chitosan microparticles for the delivery of 5-aminosalicylic acid (5-ASA) to the colon. Microparticles can spread out over a large area of colon allowing a more effective local efficacy of 5-ASA. N-Succinyl-chitosan was chosen as carrier system because of its excellent pharmaceutical properties in colon drug targeting such as poor solubility in acid environment, biocompatibility, mucoadhesive properties, and low toxicity. It was prepared by introducing succinic group into chitosan N-terminals of the glucosamine units. 5-ASA loaded NS-chitosan microparticles were prepared using spray-drying. As a control, a matrix obtained by freeze-drying techni…
Investigation of Different Iontophoretic Currents Profiles for Short-Term Applications in Cosmetics.
[EN] This study aimed at investigating the effect of electrical current profile upon the iontophoretic transport of (i) ascorbic acid (AA) and (ii) ellagic acid (EA), into porcine skin in vitro, and the impact of the physicochemical properties of both actives on their mechanism of transport when formulated in cosmetic compositions. The experiments were performed using a proprietary iontophoretic device containing a roller to apply the formulation. Three current profiles were tested: (i) galvanic direct current (DC), (ii) square unipolar pulse current (SPC), and (iii) galvanic direct current (DC) + pulse current (PC). The skin samples were collected at different sampling points, extracted an…
Pharmacokinetic models for the saturable absorption of cefuroxime axetil and saturable elimination of cefuroxime.
Since oligopeptidic drugs such as beta-lactam antibiotics share the same carriers in humans and animals, the absorption and elimination kinetics of cefuroxime (C) were investigated in rats. Plasma C concentrations were measured by liquid chromatography. Pharmacokinetics and bioavailability of C in the rat were examined after intravenous (i.v.) administration at three doses (1.78, 8.9 and 17.8mg) of cefuroxime sodium and oral administration at two doses (2.02 and 8.9mg) of cefuroxime axetil (CA). Preliminary fits using data from intravenous administration of C showed that the drug disposition kinetics were clearly nonlinear, with an increase in plasma clearance as the intravenous dose increa…
Effect of Age on Systemic Exposure and Haematological Toxicity of Carboplatin in Advanced Non-Small Cell Lung Cancer Patients
The aim of this study was to evaluate systemic exposure to carboplatin and its haematological toxicity in patients with advanced non-small cell lung cancer both older and younger than 70 years when the target area under the curve (AUC) in elderly patients was reduced by 20%. For this purpose, a population pharmacokinetic model was developed and the haema- tological toxicity of the drug was assessed. A total of 33 patients received carboplatin on day 1 and gemcitabine (1250 mg ⁄ m 2 ) on days 1 and 8. This schedule was repeated every 21 days. The Calvert-Crokcoft-Gault formula was employed to calculate a dose of carboplatin with a target AUC of 5 mg ⁄ min. ⁄ mL in patients under 70 years and…
Evaluation of ABC gene polymorphisms on the pharmacokinetics and pharmacodynamics of capecitabine in colorectal patients: Implications for dosing recommendations.
Aims The aims are to develop a population pharmacokinetic model of capecitabine (CAP) and its main metabolites after the oral administration of CAP in colorectal cancer patients with different polymorphisms of the ATP-binding cassette (ABC) gene and a population pharmacokinetic/pharmacodynamic model capable of accounting for the neutropenic effects, and to optimize the dosing strategy based on the polymorphisms of the ABC gene and/or the administration regimen as a single agent or in combination. Methods Forty-eight patients diagnosed with colorectal cancer were included, with 432 plasma levels of CAP, 5'-desoxi-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-FU), and 370 neutrophil observa…
Pharmacokinetics and absolute bioavailability of oral cefuroxime axetil in the rat.
The objectives of this study were to determine the oral bioavailability of cefuroxime (C) and to evaluate the pharmacokinetic model that best describes the plasma concentration behaviour following single intravenous (IV), intraperitoneal (IP) and oral single doses. The same dose of C was administered by IV, IP and oral routes to three separate groups of rats (2.02 mg of cefuroxime axetil (CA) by the oral route or 1.78 mg of cefuroxime sodium (CNa) by IV and IP route). A two-compartment open model without lag time can predict the C disposition kinetics. The influence of the administration route on the pharmacokinetic parameters and AUC values was investigated by means of a one-way analysis o…
Preclinical models for colonic absorption, application to controlled release formulation development.
Oral controlled release (CR) formulations have many benefits and have become a valuable resource for the local and systemic administration of drugs. The most important characteristic of these pharmaceutical products is that drug absorption occurs mainly in the colon. Therefore, this review analyses the physiological and physicochemical features that may affect an orally administered CR product, as well as the different strategies to develop a CR dosage form and the methods used to evaluate the formulation efficacy. The models available to study the intestinal permeability and their applicability to colonic permeability determinations are also discussed.
Investigating drug absorption from the colon: Single-pass vs. Doluisio approaches to in-situ rat large-intestinal perfusion
Traditionally, the colon is considered a secondary intestinal segment in the drug absorption process. However, in many cases the role of colonic drug permeability cannot be overlooked. The purpose of this research was to compare colon permeability data obtained using two different rat perfusion methods the single-pass intestinal perfusion (SPIP) approach and the closed-loop (Doluisio) perfusion model. A list of 14 structurally diverse model drugs was constructed, and their rat colon permeability was studied using the two methods. The two sets of results were compared to each other, and were evaluated vs. in-vitro, ex-vivo, and in-vivo literature values. The SPIP and the Doluisio results exh…
Impact of Undernutrition on the Pharmacokinetics and Pharmacodynamics of Anticancer Drugs: A Literature Review
The etiology of undernourishment in cancer patients is multifactorial: tumor-related mechanisms (such as obstruction, metabolic abnormalities, and functionality changes) in addition to the influence of anticancer therapies, which can induce or worsen undernutrition. The evident role of undernutrition in cancer treatment outcomes suggests the need of considering nutritional status when evaluating anticancer drugs. In order to merge the available data and offer researchers and clinicians a global view of this phenomenon, the present manuscript reviews on a drug-by-drug basis the undernutrition-related pharmacokinetic and pharmacodynamic aspects of anticancer treatments. This review notes inte…
Transdermal nortriptyline hydrocloride patch formulated within a chitosan matrix intended to be used for smoking cessation.
The aim of this study was to prepare and characterize both physically and biopharmaceutically, a nortriptyline hydrochloride (NTP-HCl) patch formulated in chitosan.16 g of each chitosan patch formulation (I, II and III, see Table 1 ) was poured onto rectangular glass plates (64 cm²) at a height of 1 mm and dried for 24 h at room temperature. In order to characterize the chitosan patches, polarized microscopy, in vitro skin permeation studies by passive diffusion and iontophoresis and rheological and bioadhesion studies were performed.Polarized microscopy revealed the absence of aggregates and crystal forms of NTP-HCl in all transdermal patches after 30 days of storage. The rheological behav…
Ion-pair approach coupled with nanoparticle formation to increase bioavailability of a low permeability charged drug.
Abstract Atenolol is a drug widely used for the treatment of hypertension. However, the great drawback it presents is a low bioavailability after oral administration. To obtain formulations that allow to improve the bioavailability of this drug is a challenge for the pharmaceutical technology. The objective of this work was to increase the rate and extent of intestinal absorption of atenolol as model of a low permeability drug, developing a double technology strategy. To increase atenolol permeability an ion pair with brilliant blue was designed and the sustained release achieved through encapsulation in polymeric nanoparticles (NPs). The in vitro release studies showed a pH-dependent relea…
Population pharmacokinetics of 5-fluorouracil in colorectal cancer patients
Aims. The pharmacokinetics of 5-fluorouracil (5-FU) after intravenous administration in color- ectal cancer patients were examined using population analysis. The relevant covariates and the extent of inter- and intraindividual variability were evaluated. Methods. Data from 27 patients with diagnosis of nonmetastatic colorectal adenocarcinoma receiving weekly 5-FU (450 mg/m2), plus levamisol 50 mg/8 hours by oral route for 3 days every 15 days, were pooled with data from 17 patients with diagnosis of metastatic colorectal adenocarcinoma, receiving daily 5-FU (425 mg/m2) and intravenous folinic acid (20 mg/m2) over five consecutive days (daily times five), every four weeks. In both groups 5-…
Characterization of intestinal absorption of C -glycoside flavonoid vicenin-2 from Lychnophora ericoides leafs in rats by nonlinear mixed effects modeling
Vicenin-2 (apigenin-6,8-di-C-β-d-glucopyranoside) is present in hydroalcoholic extracts of the Brazilian species Lychnophora ericoides Mart., Asteraceae, leaves, and the biological effects of this compound have been demonstrated including anti-inflammatory, antioxidant and anti-tumor effects in rat models. Given the potential of this compound as a pharmacological agent, the aims of this investigation were to evaluate the extent of intestinal absorption of vicenin-2, and to determine the intestinal permeation profile using an in situ single-pass intestinal perfusion technique. A validated HPLC–UV method was applied to measure the amount of unabsorbed vicenin-2 in the gut after an oral admini…