Compartmental Approach Research Articles

Population Pharmacokinetic Modelling to Support the Evaluation of Preclinical Pharmacokinetic Experiments with Lorlatinib

The effect of transporters and enzymes on drug pharmacokinetics is increasingly evaluated using genetically modified animals that have these proteins either knocked-out or their human orthologues transgenically expressed. Analysis of pharmacokinetic data obtained in such experiments is typically performed using non-compartmental analysis (NCA), which has limitations such as not being able to identify the PK parameter that is affected by the genetic modification of the enzymes or transporters and the requirement of intense and homogeneous sampling of all subjects. Here we used a compartmental population pharmacokinetic modeling approach using PK data from a series of genetically modified mouse experiments with lorlatinib to extend the results and conclusions from previously reported NCA analyses. A compartmental population pharmacokinetic model was built and physiologically plausible covariates were evaluated for the different mouse strains. With the model, similar effects of the strains on the area under the concentration-time curve (AUC) from 0 to 8 hours were found as for the NCA. Additionally, the differences in AUC between the strains were explained by specific effects on clearance and bioavailability for the strain with human expressing CYP3A4. Finally, effects of multidrug efflux transporters ATP-binding cassette (ABC) sub-family B member 1 (ABCB1) and G member 2 (ABCG2) on brain efflux were quantified. Use of compartmental population PK modeling yielded additional insight into the role of drug-metabolizing enzymes and drug transporters in mouse experiments compared to the NCA. Furthermore, these models allowed analysis of heterogeneous pooled datasets and the sparse organ concentration data in contrast to classical NCA analyses.

The compartmental approach to revision of partial knee arthroplasty results in nearer-normal gait and improved patient reported outcomes compared to total knee arthroplasty

PurposeThis study investigated the gait and patient reported outcome measures of subjects converted from a partial knee arthroplasty to combined partial knee arthroplasty, using a compartmental approach. Healthy subjects and primary total knee arthroplasty patients were used as control groups.MethodsTwenty-three patients converted from partial to combined partial knee arthroplasty were measured on the instrumented treadmill at top walking speeds, using standard gait metrics. Data were compared to healthy controls (n = 22) and primary posterior cruciate-retaining total knee arthroplasty subjects (n = 23) where surgery were performed for one or two-compartment osteoarthritis. Groups were matched for age, sex and body mass index. At the time of gait analysis, combined partial knee arthroplasty subjects were median 17 months post-revision surgery (range 4–81 months) while the total knee arthroplasty group was median 16 months post-surgery (range 6–150 months). Oxford Knee Scores and EuroQol-5D 5L scores were recorded at the time of treadmill assessment, and results analysed by question and domain.ResultsSubjects revised from partial to combined partial knee arthroplasty walked 16% faster than total knee arthroplasty (mean top walking speed 6.4 ± 0.8 km/h, vs. 5.5 ± 0.7 km/h p = 0.003), demonstrating nearer-normal weight-acceptance rate (p < 0.001), maximum weight-acceptance force (p < 0.006), mid-stance force (p < 0.03), contact time (p < 0.02), double support time (p < 0.009), step length (p = 0.003) and stride length (p = 0.051) compared to primary total knee arthroplasty. Combined partial knee arthroplasty subjects had a median Oxford Knee Score of 43 (interquartile range 39–47) vs. 38 (interquartile range 32–41, p < 0.02) and reported a median EQ-5D 0.94 (interquartile range 0.87–1.0) vs. 0.84 (interquartile range 0.80–0.89, p = 0.006).ConclusionThis study finds that a compartmental approach to native compartment degeneration following partial knee arthroplasty results in nearer-normal gait and improved patient satisfaction compared to total knee arthroplasty.Level of evidenceIII.

A model for social spreading of Covid-19: Cases of Mexico, Finland and Iceland

The shocking severity of the Covid-19 pandemic has woken up an unprecedented interest and accelerated effort of the scientific community to model and forecast epidemic spreading to find ways to control it regionally and between regions. Here we present a model that in addition to describing the dynamics of epidemic spreading with the traditional compartmental approach takes into account the social behaviour of the population distributed over a geographical region. The region to be modelled is defined as a two-dimensional grid of cells, in which each cell is weighted with the population density. In each cell a compartmental SEIRS system of delay difference equations is used to simulate the local dynamics of the disease. The infections between cells are modelled by a network of connections, which could be terrestrial, between neighbouring cells, or long range, between cities by air, road or train traffic. In addition, since people make trips without apparent reason, noise is considered to account for them to carry contagion between two randomly chosen distant cells. Hence, there is a clear separation of the parameters related to the biological characteristics of the disease from the ones that represent the spatial spread of infections due to social behaviour. We demonstrate that these parameters provide sufficient information to trace the evolution of the pandemic in different situations. In order to show the predictive power of this kind of approach we have chosen three, in a number of ways different countries, Mexico, Finland and Iceland, in which the pandemics have followed different dynamic paths. Furthermore we find that our model seems quite capable of reproducing the path of the pandemic for months with few initial data. Unlike similar models, our model shows the emergence of multiple waves in the case when the disease becomes endemic.

Structure of the information management system of cereal crops cultivation

The problems of constructing and implementing the structure of the information management system (IMS) for the cultivation of grain crops based on the optimization of the choice of agricultural technologies in view of the methods of the management theory, system and compartmental approaches are considered. The objects of management are soil, a cultivated crop and ecology of the agricultural landscape area used. It is concluded that the IMS belongs to the class of adaptive control systems with prediction by a multidimensional dynamic stochastic object. A new quality of the management system, which significantly determines its structure, is shown, namely the presence of a control loop for maintaining soil fertility and ecology in crop rotation and a control loop for the agrocenosis of the crop. A hierarchical block diagram of the object management system with forecasting is proposed, which implements functional transformations of the information flow in the IMS. As a criterion for choosing an alternative agricultural technology, environmental and economic efficiency was used, modified in view of the management goals and the composition of the machine and tractor fleet. The analytical description of the processes of the agrobiosystem at the modern level is based on the compartmental approach with the description of phenomena in the form of differential equations. The content of the compartment describes the process of energy and mass transfer in the system: soil – vegetation cover – ground layer of the air based on functional (theoretical) dynamic simulation. Based on the results of the information review, the possibility of implementation of such a management system has not been currently identified. The use of empirical simulation models in the IMS is unacceptable, since a change in a crop or natural-climatic zone will require the development of a new empirical model. The systems for simulating biophysical processes WOFOST, DSSAT, DSSAT Cropping System (CSM), APSIM and AGROTOOL, using methods of functional dynamic simulation within the framework of the compartmental approach, have been analyzed. The developed IMS structure using the AGROTOOL crop productivity model is implemented on condition that new modules of compartments are created.

Oral bioavailability and pharmacokinetics of esculetin following intravenous and oral administration in rats

Esculetin is the main active ingredient isolated from Artemisia montana (Nakai) Pamp. and Euphorbia lathyris L. The present study investigated the oral bioavailability and pharmacokinetics of esculetin in rats, following intravenous and oral administration. Twenty Sprague-Dawley rats were randomly assigned to receive 10 mg/kg of esculetin either by the intravenous or oral route. Plasma concentrations of esculetin were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental analysis as well as a compartmental modelling approach using WinNonlinTM and ADAPT 5 software, respectively. According to non-compartmental analysis, the mean oral bioavailability of esculetin was 19%. Mean ± standard deviation values of esculetin half-life, steady-state volume of distribution and clearance, following intravenous dosing, were 2.08 ± 0.46 h, 1.81 ± 0.52 L/kg and 1.27 ± 0.26 L/h/kg, respectively. As indicated by compartmental modelling, a two-compartment pharmacokinetic model with first-order absorption and elimination rate constants of 0.98 ± 0.18 h−1 and 2.47 ± 0.28 h−1, respectively, sufficiently described the plasma concentration–time curve of esculetin. Improving our understanding of the pharmacokinetic properties of esculetin could help with future development of herbal medicine products with appropriate bioactivity.

Endoscopic-assisted multi-portal compartmental resection of the masticatory space in oral cancer: Anatomical study and preliminary clinical experience

ObjectivesTo present an anatomical cadaver dissection study and our preliminary surgical experience with endoscopic-assisted multi-portal compartmental resection of the masticatory space (MS) in locally advanced oral squamous cell carcinoma (OSCC) of the retromolar area. Materials and methodsTwo fresh-frozen cadaver heads were dissected in the Laboratory of Anatomy to define the surgical steps of an endoscopic-assisted multi-portal compartmental approach to the MS. After this preclinical anatomical study, patients affected by locally advanced OSCC originating from the retromolar area with extension to the MS were prospectively enrolled and operated at two Italian referral centers for head and neck cancer between October 2019 and May 2020. ResultsSurgical technique of endoscopic-assisted multi-portal compartmental resection of the MS was preclinically defined step by step in 3 phases: transnasal, transoral/trancervical, and multi-portal. Compartmental resection of the MS was successfully completed in all specimens (4 MSs dissected). The surgical technique was subsequently applied in 3 patients affected by primary OSCC of the retromolar area, providing satisfactory results in terms of negative resection margins and local control. ConclusionsMulti-portal compartmental resection of the MS combining the transnasal and transoral/transcervical corridors is technically feasible. Such an approach to the MS in locally advanced OSCC provides different angles of incidence to the target and full control of tumor margins.

From drug evaluation to that of a path: the challenges for regulatory authorities.

To understand how the current organization of the drug evaluation leads to a compartmental vision, and what tools could be added to bring the regulatory activity closer to the goal of include the entire therapeutic path. This is an hard goal but, if we overcome the compartmental approach and open up to tools useful for planning and managing the intervention, the drug evaluation process could come to include the entire therapeutic path.

Transdermal Transport In Vitro of Domperidone by Compartmental Modeling Approach

Transdermal delivery can be alternatively chosen for domperidone to improve its low oral bioavailability. Development drugs into transdermal formulation need information about the transport mechanism of the drug. The purpose of this study was to develop models of domperidone transdermal transport in vitro based on compartmental modeling for understanding the domperidone transport mechanism. Domperidone solution (0,5 g/L in a citric buffer, pH 5) was filled into the donor compartment. The comparative study also conducted to examine the effect of different pH on domperidone transdermal transport in pH 1 (4g/L in 0,1 M HCl). The shed snake-skin and cellophane membrane were pretreated for 1 hour with chemical enhancers (oleic acid in propylene glycol) and assembled between the donor and the receptor compartment of the vertical diffusion cell. The receptor compartment was filled in with phosphate-buffered saline at a pH of 6.8. The permeation study was performed for 8 hours.&#x0D; Samples concentration was assayed by the UV-Spectrophotometry method. The cumulative permeation profiles of domperidone were analyzed using WinSAAM. Three and four-compartmental models were proposed with the one lag compartment. The evaluation of the appropriate number of compartments in the transport model was examined based on the visual goodness of fit (GOF) and the Corrected Akaike’s Information Criterion (AICc) values. Four-compartmental models with one lag compartment were the best model describing percutaneous domperidone transport either in pH donor of 5 or pH 1. The model indicates domperidone transport follows into two parallel routes, including a lag compartment.

Assessment of Strategies and Epidemiological Characteristics of Tuberculosis in Henan Province, China: Observational Study.

BackgroundIn 2005, China established an internet-based Tuberculosis Information Management System (TBIMS) to monitor changes in tuberculosis (TB). Many scholars have conducted epidemiological research using TBIMS; however, few studies assessing control strategies have been performed based on this platform data. Henan province is a high TB incidence area in China where, in addition to following the nationwide TB strategies, a series of local intervention combinations have been implemented.ObjectiveOur study aims to evaluate the impact of nationwide TB intervention combinations on epidemiological changes and determine whether Henan province can achieve the World Health Organization’s (WHO) goal of reducing TB incidence by 50% and TB mortality by 75% by the year 2025.MethodsWe used descriptive statistical methods to show the spatial and temporal distribution of pulmonary tuberculosis (PTB) reported to the TBIMS database from 2005 to 2018, and logistic regression analysis was performed to identify the risk factors of bacteriological-positive TB. The dynamic compartmental model and Bayesian melding approach was adopted to estimate the burden of TB under the impact of different TB control policies.ResultsIn total, 976,526 PTB cases were notified to the TBIMS in Henan in a period of 14 years. Although the overall incidence of PTB declined from 91.4/105 to 58.5/105, and the overall incidence of bacteriological-positive PTB declined from 44.5/105 to 14.7/105, the WHO’s 2025 goal could not be met. The distribution of high incidence and poverty-stricken counties were basically overlapped. Men, farmers and herdsmen (in rural areas), and subjects aged ≥60 years were more likely to develop bacteriological-positive PTB. The increasing treatment success for drug-susceptible tuberculosis and multidrug-resistant tuberculosis has not provided the desired reduction in incidence and mortality.ConclusionsTo achieve the targeted goal, while improving the cure rate of TB, new active (rather than passive) detection and intervention strategies should be formulated based on epidemiological characteristics in Henan province.

Effects of Carbamazepine and Phenytoin on Pharmacokinetics and Pharmacodynamics of Rivaroxaban.

Rivaroxaban (RIV) is commonly prescribed with carbamazepine or phenytoin (CBZ/PHT) in post-stroke seizure or post-stroke epilepsy patients. Although adverse events have been reported in several previous studies when they are coadministered, there are no studies of the interactions between these drugs. Therefore, our study was conducted to solve this lack of information. The potential effects of CBZ/PHT were investigated by comparing the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of RIV between the control group (RIV alone) and the test groups (RIV administered with CBZ/PHT) in rats using the noncompartmental analysis (NCA) and the compartmental model approach. The NCA results indicate that AUCt of RIV decreased by 57.9% or 89.7% and Cmax of RIV decreased by 43.3% or 70.0% after administration of CBZ/PHT, respectively. In addition, both CBZ and PHT generally reduced the effects of RIV on the prothrombin times of the blood samples. PK profiles of RIV were most properly described by a two-compartment disposition model with a mixed first- and zero-order absorption kinetics and a first-order elimination kinetics. The compartmental model approach showed that a 211% or 1030% increase in CL/F of RIV and a 33.9% or 43.4% increase in D2 of RIV were observed in the test groups by the effects of CBZ/PHT, respectively. In conclusion, CBZ and PHT significantly reduced RIV exposure and therefore reduced the therapeutic effects of RIV. Consequently, this might result in adverse events due to insufficient RIV concentration to attain its therapeutic effects. Further studies are needed to validate this finding.

Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis

BackgroundRecent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers. MethodsThree increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time–plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach. ResultsThe pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics. ConclusionsThe model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites. Clinical trial registrationDutch Cochrane Center 5359.

SIRD Model of the Time Progression of Excess Deaths in NYC, the Total US, and Sweden Observed in the Spring of 2020

Using a Susceptible-Infected-Recovered-Dead compartmental model approach, the time progression of excess deaths in NYC, the total US, and Sweden observed in the Spring of 2020 is modeled using variable-in-time second-order kinetics representing infection caused by social interaction followed by constant-in-time first-order kinetics representing the progression of the disease through various stages. The model is able to represent, at the $25 \%$ level, a combined dataset of weekly deaths per 100,000 population from NYC, the total US and Sweden as well as single points estimates of the number recovered from Covid-19 in NYC and Sweden. The time progression of the disease from infected to recovery or death is the same for the three populations, indicating that the disease underlying excess deaths is the same. According to this model, given this dataset, for the disease to be incapable of spreading in the population the fraction fRcrit of the population that are not susceptible (having antibodies) must be greater than 0.2 assuming social interactions as in NYC. This provides an estimate of the recovered fraction in the population needed for herd immunity, assuming the degree of closeness of social interactions as in NYC. For less close populations, the threshold for herd immunity would be lower.

Epidemic dynamics of influenza-like diseases spreading in complex networks

Population contact pattern plays an important role in the spread of an infectious disease. This can be described in the framework of a complex network approach. In this paper network epidemic models for influenza-like diseases that may have infectious force in incubative or asymptomatic stage are formulated and studied. Two general types of network models are considered: the annealed and the quenched networks. The next-generation matrix approach is employed to compute the basic reproduction number of our network-based models. The implicit equations for the final epidemic size are derived, and the existence and uniqueness of solutions for implicit equations are studied by rewriting implicit equations as suitable fixed-point problems. In particular, for networks with no degree correlation, low-dimensional systems of nonlinear ordinary differential model are derived by employing an edge-based compartmental approach. Due to their low dimension, a gap between the parameter identification problem for influenza-like diseases or network inference and network epidemic models may be built through our results. The analysis is applied to an example of influenza epidemic based on the final epidemic size, from which the transmission rate and the basic reproduction number can be estimated.

Transmission Dynamics of COVID-19 in Bangladesh - A Compartmental Modeling Approach

The coronavirus disease (COVID-19) was first identified in Bangldesh, on March 8, 2020. As of May 15, there are 20065 confirmed COVID-19 cases, including 3882 patients who have recovered and 298 related deaths. The objective of this study is to examine the transmission dynamics of COVID-19 and predict the growth of the infection in Bangladesh using the publicly available data though a mathematical model. The suscected-exposed-infectious-recoverd-dead (SEIRD) model is employed to describe the dynamics based on the kinematic parameters fitted on the data for the outbreak in Bangladesh up to May 15. The expression of basic reproduction number R_0 using the next generating matrix is derived and estimated. The kinematic parameters that describe primary transmission rate (0.045), recovery rate (0.03) and death rate (0.01) seems to be lower, respective of other countries. Based on the official counts for confirmed cases, the simulations suggest that the cumulative number of active infected follows an exponential trend. The basic reproduction number is 2.85 (95% CI :2.66-3.04) and transmission trends clearly indicates the outbreak of COVID-19 in Bangladesh. There is now breakneck concern regarding the capacity to respond to needs of infected patients effectively and to prevent this pandemic from further spreading in Bangladesh, one of the densest countries in the world.

Linking CFD and Kinetic Models in Anaerobic Digestion Using a Compartmental Model Approach

Understanding mixing behavior and its impact on conversion processes is essential for the operational stability and conversion efficiency of anaerobic digestion (AD). Mathematical modelling is a powerful tool to achieve this. Direct linkage of Computational Fluid Dynamics (CFD) and the kinetic model is, however, computationally expensive, given the stiffness of the kinetic model. Therefore, this paper proposes a compartmental model (CM) approach, which is derived from a converged CFD solution to understand the performance of AD under non-ideal mixing conditions and with spatial variation of substrates, biomass, pH, and specific biogas and methane production. To quantify the effect of non-uniformity on the reactor performance, the CM implements the Anaerobic Digestion Model 1 (ADM1) in each compartment. It is demonstrated that the performance and spatial variation of the biochemical process in a CM are significantly different from a continuously stirred tank reactor (CSTR) assumption. Hence, the assumption of complete mixed conditions needs attention concerning the AD performance prediction and biochemical process non-uniformities.

Dynamics of the competition between two languages

This paper reports a new kind of mathematical model for language competition dynamics using compartmental epidemiological modeling approach. The model describes the competition between two languages, say the predominant one called language 1, and the less spoken language 2, both in the same community. We distinguish three groups of population building the concerned community: one majority speaking language 1, one minority speaking language 2 and a last minority speaking neither language 1 nor language 2. The study of the proposed model includes an analysis of the evolution of the number of speakers over time. This model predicts that language 2 can inevitably disappear if the threshold parameter $${\mathcal {R}}_0$$ is less than one. We show that our model is well-posed mathematically and linguistically. We also show that the model has basically two linguistic equilibrium points. A monolingual equilibrium point that corresponds to the case where only one language is spoken: some individuals speak only the language 1 and some others do speak neither language 1, nor language 2. A bilingual equilibrium point which corresponds to the case where all the languages are spoken: some individuals speak both languages 1 and 2, some others speak only language 1, while a third group does speak only language 2, and the last group speaks none of the two languages. In this bilingual equilibrium point, both languages coexist. Depending on the threshold parameter, we demonstrate the stability of these equilibria. The model presents on one hand, a direct bifurcation phenomenon, in which we have a stable equilibrium point without bilingual speakers when the associated basic reproduction number is less than one. On the other hand, it presents a stable bilingual equilibrium point when the number of associated basic reproductions is greater than one. The analysis of the overall sensitivity of the model is performed and the impact of the system parameters on the basic reproduction number was performed using sensitivity analysis to determine the impact of each parameter of the system on bilingualism. The numerical simulations carried out are in agreement with the presented theory

Predictive engines based on pharmacokinetics modelling for tacrolimus personalized dosage in paediatric renal transplant patients

The development of predictive engines based on pharmacokinetic-physiological mathematical models for personalised dosage recommendations is an immature field. Nevertheless, these models are extensively applied during the design of new drugs. This study presents new advances in this subject, through a stable population of patients who underwent kidney transplantation and were prescribed tacrolimus. We developed 2 new population pharmacokinetic models based on a compartmental approach, with one following the physiologically based pharmacokinetic approach and both including circadian modulation of absorption and clearance variables. One of the major findings was an improved predictive capability for both models thanks to the consideration of circadian rhythms, both in estimating the population and in Bayesian individual customisation. This outcome confirms a plausible mechanism suggested by other authors to explain circadian patterns of tacrolimus concentrations. We also discovered significant intrapatient variability in tacrolimus levels a week after the conversion from a fast-release (Prograf) to a sustained-release formulation (Advagraf) using adaptive optimisation techniques, despite high adherence and controlled conditions. We calculated the intrapatient variability through parametric intrapatient variations, which provides a method for quantifying the mechanisms involved. We present a first application for the analysis of bioavailability changes in formulation conversion. The 2 pharmacokinetic models have demonstrated their capability as predictive engines for personalised dosage recommendations, although the physiologically based pharmacokinetic model showed better predictive behaviour.

Modeling and optimized controller for cardiac drug infusion system

Background: Manual drug infusion during surgeries is inaccurate and timeconsuming which has been adopted technique in most of the hospitals. Methods: Based on clinical data, it is evident that the manual control is inaccurate and takes prolonged time to bring into effect, if any change in infusion rate is required during clinical practice. Considering this drawback, the modeling of cardiovascular system (CVS) and baroreceptor (BR) is developed using miscellaneous differential equations based on compartmental approach. The control variables are mean arterial pressure (MAP) and cardiac output (CO) obtained from CVS-BR model. Findings: The manipulated variables are noradrenaline (NAR) and nitroglycerine (NG) infusion rate which is modeled using the relationship between volume and drug mass effect equations on CVS-BR model. For the open loop transfer function derived from the model, relative gain array (RGA) analysis is performed to identify the influence of maximum effect of manipulated variables on the physiological parameters. The simulation results obtained from MATLAB are correlated using time domain specifications and error criteria. The performance index reveals the least error and facilitates in accurate infusion of drugs to the patient during cardiovascular surgeries. Novelty: The automatic controller during surgery provides safe operating condition and speedy recovery of the patients and also helps the anaesthetist to monitor and regulate the physiological variables. Keywords: Control strategy; Error criteria; Drug infusion; Modeling; Relative gain array; Simulation

Ocular Intracameral Pharmacokinetics for a Cocktail of Timolol, Betaxolol, and Atenolol in Rabbits.

The mechanisms of drug clearance from the aqueous humor are poorly defined. In this study, a cocktail approach was used to simultaneously determine the pharmacokinetics of three β-blocker agents after intracameral (ic) injection into the rabbit eyes. Aqueous humor samples were collected and analyzed using LC-MS/MS to determine drug concentrations. Pharmacokinetic parameters were obtained using a compartmental fitting approach, and the estimated clearance, volume of distribution, and half-life values were the following: atenolol (6.44 μL/min, 687 μL, and 73.87 min), timolol (19.30 μL/min, 937 μL, and 33.64 min), and betaxolol (32.20 μL/min, 1421 μL, and 30.58 min). Increased compound lipophilicity (atenolol < timolol < betaxolol) resulted in higher clearance and volume of distributions in the aqueous humor. Clearance of timolol and betaxolol is about 10 times higher than the aqueous humor outflow, demonstrating the importance of other elimination routes (e.g., uptake to iris and ciliary body and subsequent elimination via blood flow).

Assessment of the effect of polymers combination and effervescent component on the drug release of swellable gastro-floating tablet formulation through compartmental modeling-based approach

The aim of this research was to assess the effect of polymer blend and effervescent components on the floating and swelling behaviors of swellable gastro-floating formulation as well as the drug release through a compartmental modeling analysis. Swellable gastro-floating formulation of freely water-soluble drug, metformin HCl as a drug model, was formulated and developed using D-optimal design. Polymer combination between interpolymer complex (IPC) (poly-vinyl acetate-copolymer methacrylate) and hydroxy propyl methyl cellulose (HPMC), and effervescent components were studied and optimized in this work. Several factors affecting the drug release behavior were determined e.g. swelling behavior, erosion behavior, and floating behavior were studied as well as the drug release through compartmental modeling analysis. The results revealed that the hydrophilic polymer was responsible for gas entrapment formed from effervescent reaction, meanwhile IPC contributed on maintaining the swollen matrix integrity through intermolecular polymer interaction. In addition, effervescent components played fundamental role in the formation of porous system as well as inducing burst release effect. Compartmental modeling provided different outlook about the drug release. Presence of IPC at a high proportion (10–15%) of the polymer blend modulated the changes of pattern of the drug release kinetics and mechanism. Finally, compartmental modeling-based approach was more adequate to describe the drug release kinetics and mechanism compared to the monophasic equation model correlating with process understanding of the drug release from swellable gastro-floating formulation.