The Critical Role of Mechanism-Based Models for Understanding and Predicting Liposomal Drug Loading, Binding and Release Kinetics

Liposomal delivery systems hold considerable promise for improvement of cancer therapy provided that critical formulation design criteria can be met. The main objective of the current project was to enable quality by design in the formulation of liposomal delivery systems by developing comprehensive, mechanism-based mathematical models of drug loading, binding and release kinetics that take into account not only the therapeutic requirement but the physicochemical properties of the drug, the bilayer membrane, and the intraliposomal microenvironment. Membrane binding of the drug affects both drug loading and release from liposomes. The influence of bilayer composition and phase structure on the partitioning behavior of a model non-polar drug, dexamethasone, and its water soluble prodrug, dexamethasone phosphate, was evaluated. Consequently, a quantitative dependence of the partition coefficient on the free surface area of the bilayer, a property related to acyl chain ordering, was noted. The efficacy of liposomal formulations is critically dependent on the drug release rates from liposomes. However, various formulation efforts to design optimal release rates are futile without a validated characterization method. The pitfalls of the commonly used dynamic dialysis method for determination of apparent release kinetics from nanoparticles were highlighted along with the experimental and mathematical approaches to overcome them. The value of using mechanism-based models to obtain the actual rate constant for nanoparticle release was demonstrated. A novel method to improve liposomal loading of poorly soluble ionizable drugs using supersaturated drug solutions was developed using the model drug AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin), a poorly soluble camptothecin analogue. Enhanced loading with a drug to lipid ratio of 0.17 was achieved and the rate and extent of loading was explained by a mathematical model that took into account the chemical equilibria inside and outside the vesicles and the transport kinetics of various permeable species across the lipid bilayer and the dialysis membrane. Tunable liposomal release kinetics would be highly desirable to meet the varying therapeutic requirements. A large range of liposome release half-lives from 1 hr to 892 hr were obtained by modulation of intraliposomal pH and lipid composition using dexamethasone phosphate as a model ionizable drug. The mathematical models developed were successful in accounting for the change in apparent permeability with change in intraliposomal pH and bilayer free surface area. This work demonstrates the critical role of mechanism-based models in design of liposomal formulations

IMI – Oral Biopharmaceutics Tools project – Evaluation of Bottom-up PBPK Prediction Success Part 2: An Introduction to the Simulation Exercise and Overview of Results

Orally administered drugs are subject to a number of barriers impacting bioavailability (F-oral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp (R), and GastroPlus (TM)) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, F-oral and relative AUC (F-rel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.</p

IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes

Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.</p

Implementation of Corporate Governance Norms in Select Indian Industries – A Case Study

This paper deals with the analysis of the implementation of corporate governance norms in the Indian industries. The analysis has been done for the sample companies falling into different categories of industry, in regard to the corporate governance reporting practices during the period of study. In the study it has been observed that the implementation of the corporate governance principles in the system and their reporting in the annual reports has been gradually and slowly incarnated into the corporate conscience to exude transparency, openness and accountability. The study in this period has covered compliance of the codes of corporate governance practices.</jats:p

An approach to treatment modalities of keloids: a comparative study

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; In spite of the presence of such an array of treatment modalities, none of these can be claimed to be an ideal treatment option as most of them have limited efficacy, significant side effects or increased chances of recurrence. Hence the study was undertaken to search an ideal treatment for keloids which is safe, effective, and with low rate of recurrence.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; Total of 200 patients were recruited out of which only 160 patients were included in study. The patients were divided into three groups and administered with different modes of treatment. Patients in all the groups were followed up at 3 weekly intervals for evaluation of response. At the end of the study, the data was compiled and analysed using appropriate statistical tests.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; In only 32 patients completed study in group 1, 2 and 3 respectively. Group 1, 2 and 3 were more or less equally efficacious with clearance rate. Complete clearance was seen in 24 patients in group 1 patients, in group 2 there were 22 patients with complete clearance and in group 3 there were 24 patients.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; Intralesional triamcinolone acetonide, intralesional triamcinolone acetonide with hyaluronidase and intralesional radiofrequency with intralesional triamcinolone acetonide are almost equally effective modalities for the treatment of keloids. But, intralesional triamcinolone acetonide with hyaluronidase fares better than other two as far as safety is concerned with least side effects.&lt;/p&gt;&lt;p class="after-h2"&gt; &lt;/p&gt;</jats:p