Drug Distribution Process Research Articles

Methods to Predict Volume of Distribution.

Prior to human studies, knowledge of drug disposition in the body is useful to inform decisions on drug safety and efficacy, first in human dosing, and dosing regimen design. It is therefore of interest to develop predictive models for primary pharmacokinetic parameters, clearance, and volume of distribution. The volume of distribution of a drug is determined by the physiological properties of the body and physiochemical properties of the drug, and is used to determine secondary parameters, including the half-life. The purpose of this review is to provide an overview of current methods for the prediction of volume of distribution of drugs, discuss a comparison between the methods, and identify deficiencies in current predictive methods for future improvement. Several volumes of distribution prediction methods are discussed, including preclinical extrapolation, physiological methods, tissue composition-based models to predict tissue:plasma partition coefficients, and quantitative structure-activity relationships. Key factors that impact the prediction of volume of distribution, such as permeability, transport, and accuracy of experimental inputs, are discussed. A comparison of current methods indicates that in general, all methods predict drug volume of distribution with an absolute average fold error of 2-fold. Currently, the use of composition-based PBPK models is preferred to models requiring in vivo input. Composition-based models perfusion-limited PBPK models are commonly used at present for prediction of tissue:plasma partition coefficients and volume of distribution, respectively. A better mechanistic understanding of important drug distribution processes will result in improvements in all modeling approaches.

Electrochemistry of Antibiotic Hybrids: Towards the Detection and Quantification of Antibiotic Resistance

The overuse of antibiotics in human and veterinary medicine as well as in agriculture has caused antibiotic resistance to become a global problem and national and international health organizations have called for the urgent development of new treatment strategies. The increase of antibiotic resistance in Gram-negative bacteria in particular is a major cause for concern, as many Gram-negatives cause serious infections, such as pneumonia, and only few effective antibiotics have been developed due to bacterial innate defense mechanisms, including low outer membrane permeability and high number of efflux pumps. The presented study demonstrates the thorough electrochemical characterization of antibiotic hybrid drugs, currently under development at the University of Manitoba, Canada. The interaction of these antibiotic hybrids with selected biomolecules is investigated to further our understanding about in vivo processes of drug absorption, distribution, metabolism, and excretion. Furthermore, the interaction of bacteria with the newly developed investigational antibacterial therapeutics is studied towards the quantification of antibiotic resistance in pathogens to address the dire need for innovative strategies that are able to quantify efflux and influx of agents into bacterial cells for the assessment of potential new and reliable antimicrobial candidates.

The mechanisms of pharmacokinetic food-drug interactions – A perspective from the UNGAP group

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group “Food-Drug Interface”, the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives.

A Kinetic Approach to Determining Drug Distribution in Complex Biphasic Systems

Pharmaceutical emulsions contain multiple components, such as micellar, aqueous, and oil phases, leading to complex drug transfer and equilibrium phenomena. These complex components present challenges for the bioequivalence assessment of the drug products. The objective of the study was to develop a method that can probe the underlying mechanism and process of drug distribution. The concept of drug partitioning into biphasic systems was used to simplify the complex transfer phenomenon. A kinetic method was developed taking into account the biphasic diffusion. Using this approach, both the rate (kinetics) and the extent (equilibrium) of distribution can be determined. For method development purpose, 3 model compounds (triamcinolone acetonide, difluprednate, and cyclosporine), with expected partition coefficient values ranging from 2 to 6, were tested using the kinetic method and the traditional shake-flask method. The values obtained by the 2 methods for all compounds correlated well (r2 = 0.825). Various organic and aqueous solvents which are commonly encountered in formulations were also tested to determine the impact of phase composition on drug distribution. The kinetic method was found to offer more flexibility in terms of solvent composition and can lead to better understanding for drug distribution and potential drug release in complex biphasic systems.

Developmental Changes in Pharmacokinetics and Pharmacodynamics

Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug-response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics.

Sécurisation de la dispensation individuelle et nominative suite à l’implantation d’un automate de dispensation nominative : cartographie des risques a priori au sein d’une pharmacie à usage intérieur

With a view to reinforcing the security of the drug distribution process, the hospital pharmacy has decided to automate the patient-specific unit dose distribution system which, up to now was performed manually, through the acquisition of a unit dose dispensing system: the ACCED S 300 (ECODEX®). The aim of this work is to realize a cartography of risks, focused on the dispensing stage, prior to the implementation of the automated system. A multidisciplinary group applied the preliminary risk analysis (PRA) technique. The study was limited to the dispensing stage of unit doses within the hospital pharmacy. This analysis revealed 122accident scenarii, including 18with an initial unacceptable criticality (14.8% of scenarii). In total, 140risk management actions were proposed. These actions include: acquisition of equipment, communication and training of pharmacy staff, communication with services, human resources management and organization of working hours, writing and updating quality documents, programming the software and interfaces linked with the robot. The implementation of risk management actions should reduce the risk and contribute to avoiding the most critical scenarii. This will require the availability of human and financial resources and the implication of management.

Pharmacovigilance in China: development and challenges.

Background Rational drug use and drug safety are becoming increasingly important concerns in China with the increasing public access to drugs and the health-care system, and this has led to the development of pharmacovigilance in China. Aim of the review To provide a brief introduction about pharmacovigilance in China in terms of system development, utilization and challenges. Method Relevant studies on pharmacovigilance related to the study aim was undertaken through literature search to synthesize the extracted data. Results The creation and evolvement of China's pharmacovigilance system spans across 30years since 1989. The system consists of four progressing administrative layers: county, municipal, provincial and national levels. China has passed over 20 laws and regulations related to pharmacovigilance covering the processes of drug development, manufacture, distribution and use with the aim to guard drug safety. An online spontaneous self-reporting Adverse Drug Reaction (ADR) Monitoring System was established in 2003. ADRs are mainly reported by medical institutions, pharmaceutical manufacturers, and drug distributors. Currently there is no mandatory ADR reporting requirement for pharmaceutical manufacturers, and a proposed regulation under public comment will likely change this. China has started to build active pharmacovigilance surveillance programs in addition to the passive ADR reporting system. The China Food and Drug Administration has established the intensive Safety Monitoring Program and the National Adverse Drug Reaction Monitoring Sentinel Alliance Program based on electronic health records to further the efforts of ADR reporting, monitoring and analysis. Conclusion The practice of ADR monitoring and pharmacovigilance in China have made great progress. More efforts are needed both in system building, and creation of laws and regulations to strengthen the safe use of medicines.

Phospholipid-based Immobilized Artificial Membrane (IAM) Chromatography: A Powerful Tool to Model Drug Distribution Processes.

A review of applications of the Immobilized Artificial Membrane (IAM) chromatography in drug discovery is given. IAM chromatography is presented as a tool to predict the interactions of solutes with biomembranes, blood-brain barrier permeability, volume of distribution, oral and skin absorption of drugs and compared to other in vitro techniques used to study drug bioavailability (caco-2 cells, liposome partition). Unbound phosphatidylcholine based stationary phases are also discussed. Some new trends and ideas in the IAM chromatography are presented.

Organizational ethnography of direct drugs distribution in Parma AUSL.

The locations where healthcare organizations directly distribute medications to patients in specific circumstances, such as at hospital discharge, are settings at risk of professional errors. Using organizational ethnography methodology, we sought to explore the characteristics of points of direct distribution of drugs (PDD) in the AUSL of Parma and identify aspects of the delivery process that could potentially generate errors. We conducted 75 3-hour observations (225 hours at total) of the two Parma AUSL PDDs. The nature of the observations was known by PDD professionals but blinded to PDD patients. In one PDD, we shadowed the pharmacist responsible for the entire drug distribution process, as well as followed the pattern of drug packaging from the Centralized Logistic Pharmacy Unit in Reggio Emilia to the Parma Pharmaceutical Department. In the other PDD, we carried out observations in the patient waiting room and conducted interviews with patients and PDD professionals. Collected data were evaluated via content analysis and study results were presented to the study-working group for further discussion. Research findings highlighted a limited number of errors in drug delivery process. The most frequently observed errors by pharmacists were incorrect interpretation of prescriptions, dispensation of wrong dosage, and failure to deliver a prescribed drug to the patient. Potential sources of error were repeated interruptions of the pharmacist workflow, such as phone calls, helping colleagues in emergency situations and serving an excessive number of patients. Based on these results, the study-working group proposed logistical and organizational modifications of PDD and delivery process to improve quality and reduce risks.

NATIONAL HEALTH COVERAGE SYSTEM : PHARMACISTS AND JKN PARTICIPANT SATISFACTION IN PRIMARY HEALTH FACILITIES

National Health Insurance is a health protection system for participants to obtain health care benefits and protection to meet basic health needs that organized based on social insurance and equity principles. JKN in cooperation with the primary health facilities to provide comprehensive health services including pharmacy services. Pharmacist responsible for drug availability and affordability that affected by drug procurement process, drug distribution process, and drug cost claiming process.This research’s aim to determine relationship between national health insurances services to pharmacists satisfaction and to determine relationship between pharmacy services to outpatient satisfaction at primary health facilities. Data used in research are primary data that collected through questionnare and interview. The method used is purposive sampling which the data is analyzed using linear and multiple regresion and see significant value (p). The number of respondents was 40 pharmacists and 150 patients in health centers and primary clinics scattered in Sleman, Bantul, and Kota Yogyakarta. The results showed that the process of procurement and distribution of drugs have a relationship with a pharmacist satisfaction while drug costs not process claims with consecutive p 0.010, 0.002, and 0.261. Related to the satisfaction of the outpatient pharmacy services result there is a relationship of drug availability (p = 0.003), service time (p = 0.006), and get drug (p = 0.000) to the satisfaction of outpatients. The conclusion of this study is the process of procurement and distribution of drugs have a relationship with a pharmacist satisfaction. In addition, the availability of pharmacy services such as medication, a drug services, and the provision of drug information also has a significant relationship to the satisfaction of outpatients in health facilities first rate. Keywords: pharmacy services, pharmacists, patients, JKN

Interaction between CYP450 enzymes and metabolism of traditional Chinese medicine as well as enzyme activity assay

Drugs are exogenous compounds for human bodies, and will be metabolized by many enzymes after administration. CYP450 enzyme, as a major metabolic enzyme, is an important phase I drug metabolizing enzyme. In human bodies, about 75% of drug metabolism is conducted by CYP450 enzymes, and CYP450 enzymes is the key factor for drug interactions between traditional Chinese medicine( TCM) -TCM, TCM-medicine and other drug combination. In order to make clear the interaction between metabolic enzymes and TCM metabolism, we generally chose the enzymatic activity as an evaluation index. That is to say, the enhancement or reduction of CYP450 enzyme activity was used to infer the inducing or inhibitory effect of active ingredients and extracts of traditional Chinese medicine on enzymes. At present, the common method for measuring metabolic enzyme activity is Cocktail probe drugs, and it is the key to select the suitable probe substrates. This is of great significance for study drug's absorption, distribution, metabolism and excretion (ADME) process in organisms. The study focuses on the interaction between TCMs, active ingredients, herbal extracts, cocktail probe substrates as well as CYP450 enzymes, in order to guide future studies.

The drug logistics process: an innovative experience

Purpose – The purpose of this paper is to present the latest innovations in the drug distribution processes of hospital companies, which are currently dealing with high inventory and storage costs and fragmented organizational responsibilities. Design/methodology/approach – The literature review and the in-depth analysis of a case study support the understanding of the unit dose drug distribution system and the subsequent definition of the practical implications for hospital companies. Findings – Starting from the insights offered by the case study, the analysis shows that the unit dose system allows hospitals to improve the patient care quality and reduce costs. Research limitations/implications – The limitations of the research are those related to the theoretical and exploratory nature of the study, but from a practical point of view, the work provides important indications to the management of healthcare companies, which have to innovate their drug distribution systems. Originality/value – This paper analyzes a new and highly topical issue and provides several insights for the competitive development of a fundamental sector.

Matrix trace operators: from spectral moments of molecular graphs and complex networks to perturbations in synthetic reactions, micelle nanoparticles, and drug ADME processes.

The study of quantitative structure-property relationships (QSPR) is important to study complex networks of chemical reactions in drug synthesis or metabolism or drug-target interaction networks. A difficult but possible goal is the prediction of drug absorption, distribution, metabolism, and excretion (ADME) process with a single QSPR model. For this QSPR modelers need to use flexible structural parameters useful for the description of many different systems at different structural scales (multi-scale parameters). Also they need to use powerful analytical methods able to link in a single multi-scale hypothesis structural parameters of different target systems (multi-target modeling) with different experimental properties of these systems (multi-output models). In this sense, the QSPR study of complex bio-molecular systems may benefit substantially from the combined application of spectral moments of graph representations of complex systems with perturbation theory methods. On one hand, spectral moments are almost universal parameters that can be calculated to many different matrices used to represent the structure of the states of different systems. On the other hand, perturbation methods can be used to add "small" variation terms to parameters of a known state of a given system in order to approach to a solution of another state of the same or similar system with unknown properties. Here we present one state-of-art review about the different applications of spectral moments to describe complex bio-molecular systems. Next, we give some general ideas and formulate plausible linear models for a general-purpose perturbation theory of QSPR problems of complex systems. Last, we develop three new QSPR-Perturbation theory models based on spectral moments for three different problems with multiple in-out boundary conditions that are relevant to biomolecular sciences. The three models developed correctly classify more than pairs 115,600; 48,000; 134,900 cases of the effects of in-out perturbations in intra-molecular carbolithiations, drug ADME process, or self-aggregation of micelle nanoparticles of drugs or surfactants. The Accuracy (Ac), Sensitivity (Sn), and Specificity (Sp) of these models were >90% in all cases. The first model predicts variations in the yield or enantiomeric excess due to structural variations or changes in the solvent, temperature, temperature of addition, or time of reaction. The second model predicts changes in >18 parameters of biological effects for >3000 assays of ADME properties and/or interactions between 31,723 drugs and 100 targets (metabolizing enzymes, drug transporters, or organisms). The third model predicts perturbations due to changes in temperature, solvent, salt concentration, and/or structure of anions or cations in the self-aggregation of micelle nanoparticles of drugs and surfactants.

A unique drug distribution process for radium Ra 223 dichloride injection and its implication for product quality, patient privacy, and delineation of professional responsibilities.

On May 15, 2013, Bayer Healthcare Pharmaceuticals announced that it had received marketing approval for the therapeutic radioactive medication radium Ra 223 dichloride injection (Xofigo; Ra 223). The product acquisition and distribution process for hospital-based nuclear pharmacies and nuclear medicine services is unlike any other. The product is distributed as a low-risk compounded sterile preparation through a single compounding nuclear pharmacy located in Denver, Colorado, pursuant to a prescription. This model for drug distribution and delivery to the user institution has implications for product quality, patient privacy, and delineation of professional responsibilities.

First pass intestinal and liver metabolism of paracetamol in a microfluidic platform coupled with a mathematical modeling as a means of evaluating ADME processes in humans.

We developed a microfluidic platform to investigate paracetamol intestinal and liver first pass metabolism. This approach was coupled with a mathematical model to estimate intrinsic in vitro parameters and to predict in vivo processes. The kinetic modeling estimated the paracetamol and paracetamol sulfate permeabilities, the sulfate and glucuronide effluxes in the intestine compartment. Based on a gut model, we estimated intrinsic intestinal clearance of between 26 and 77 L/h for paracetamol in humans, a permeability of 10 L/h, and a gut availability between 0.17 and 0.53 (compared to 0.95-1 in vivo). The role played by the liver in paracetamol metabolism was estimated via in vitro intrinsic clearances of 7.6, 13.6, and 11.5 µL/min/10(6) cells for HepG2/C3a, rat primary hepatocytes, and human primary hepatocytes, respectively. Based on a parallel tube model to describe the liver, the paracetamol hepatic clearance, and the paracetamol hepatic availability in humans were estimated at 6.5 mL/min/kg of bodyweight (BDW) and 0.7, respectively (when compared to 5 mL/min/kg of BDW and 0.77 to 0.88 for in vivo values, respectively). The drug availability was predicted ranging between 0.24 and 0.41 (0.88 in vivo). The overall approach provided a first step in an integrated strategy combining in silico/in vitro methods based on microfluidic for evaluating drug absorption, distribution and metabolism processes.

Thermodynamic Approaches to the Challenges of Solubility in Drug Discovery and Development

This paper considers fundamental aspects determining the processes of drug compound dissolution and distribution in solvents/systems modeling biological media. Special attention is paid to the complex analysis of thermodynamic functions of sublimation and solvation/hydration processes during structural modification of lead/hit compounds and their influence on dissolution processes. The paper shows that at the first stages of drug design it is necessary to develop algorithms of optimizing the properties determining absorption, distribution, metabolism, and excretion (ADME) characteristics of molecules: in particular, diffusion flux density through lipophilic membranes. Using sulfonamides and nonsteroidal anti-inflammatory drugs (NSAIDs) as an example, we have demonstrated the efficiency of approaches to manipulating thermodynamic functions of the basic processes that result from delivering compounds to the points of their operation. We have formulated several criteria of compound selection for further tests.

P6.029 Antiretroviral Therapy (ART) Programme in Bangladesh: Increasing National Ownership

BackgroundThe first HIV positive case was detected back in 1989. From then 2,871 cases have been reported till December 2012. However, the estimated number of PLHIV in Bangladesh is 7,500....

Physiologically-Based Pharmacokinetics in Drug Development and Regulatory Science

The application of physiologically-based pharmacokinetic (PBPK) modeling is coming of age in drug development and regulation, reflecting significant advances over the past 10 years in the predictability of key pharmacokinetic (PK) parameters from human in vitro data and in the availability of dedicated software platforms and associated databases. Specific advances and contemporary challenges with respect to predicting the processes of drug clearance, distribution, and absorption are reviewed, together with the ability to anticipate the quantitative extent of PK-based drug-drug interactions and the impact of age, genetics, disease, and formulation. The value of this capability in selecting and designing appropriate clinical studies, its implications for resource-sparing techniques, and a more holistic view of the application of PK across the preclinical/clinical divide are considered. Finally, some attention is given to the positioning of PBPK within the drug development and approval paradigm and its future application in truly personalized medicine.

Pharmacist characteristics, medication use perceptions, and professional satisfaction: a first national survey in the state of Qatar

Pharmacist characteristics, medication use perceptions, and professional satisfaction: a first national survey in the state of Qatar Maguy Saffouh El Hajj1, Nadir Kheir1, Manal Zaidan2, Peter J Jewesson11College of Pharmacy, Qatar University, Doha, Qatar; 2Pharmacy Department, Al Amal Cancer Centre, Doha, QatarPurpose: To characterize the professional demographics, opinions about the medication use process, perceived public satisfaction with pharmacy services, and professional satisfaction of pharmacists practicing in the state of Qatar.Materials and methods: The study was designed as a hypothesis-generating, online, anonymous, opinion survey of practicing pharmacists in Qatar.Results: Two hundred and sixty-four survey accesses were recorded during the 6-week study period, and 250 surveys containing responses to one or more questions were included in the analysis. Eighty-four percent of respondents reported graduating at least 5 years prior to the survey, and 86% held a baccalaureate degree in pharmacy as their highest degree. The most common source of the highest degree was one of five countries (Egypt, Jordan, India, Sudan, or Pakistan). Forty-five percent of respondents were working in a hospital setting, and 33% were in a community pharmacy. The lowest incidence of agreement across the 10 drug procurement and distribution process statements was observed for the adequacy of medication supplies statements (33% of all respondents). The highest incidence of agreement across the eight medication use process statements was for the statement pertaining to infrequent dispensing errors (68%), and the lowest incidence of agreement was observed for the statement pertaining to the adequacy of patient monitoring (30%). The pharmacist was chosen as the best candidate to resolve perceived unmet medication needs for four of eight statements, whereas physicians were most frequently chosen for three of the four remaining statements. Respondents' perceptions regarding patient satisfaction with the different elements of the medication use process revealed that the lowest incidence of agreement pertained to patients' satisfaction with the waiting time required to obtain their medications (35%). Forty percent of all respondents rated themselves as professionally dissatisfied. Improvements to their professional role, greater opportunities for professional development, and enhancements in human resource-related conditions were identified as potential remedies to this situation.Conclusion: This study represents the first known attempt to formally solicit the opinions of pharmacists in Qatar. The study results have provided valuable information regarding the demographic characteristics, pharmacist perceptions about the medication use process, and professional satisfaction of practicing pharmacists in the country. This information is being utilized to guide workforce planning, to help identify potential shortcomings in the health care system, and to better understand continuing education and professional satisfaction needs of Qatar's pharmacy practitioners. We encourage other countries to conduct similar surveys in order to better understand the characteristics, perceptions, and needs of their health care workers.Keywords: pharmacist, characteristics, medication use, perceptions, professional satisfaction

Drawing and interpreting data: Children's impressions of onchocerciasis and community-directed treatment with ivermectin (CDTI) in four onchocerciasis endemic countries in Africa

Although the depiction of a child leading a blind man is the most enduring image of onchocerciasis in Africa, research activities have hardly involved children. This paper aims at giving voice to children through drawings and their interpretation. The study was conducted in 2009 in Cameroon, Democratic Republic of Congo (DRC), Nigeria and Uganda. Children aged 6–16 years were asked to draw their perceptions of onchocerciasis and community-directed treatment with ivermectin (CDTI) in their communities. A total of 50 drawings were generated. The drawings depicted four main aspects of onchocerciasis: (1) the disease symptoms, (2) the negative consequences of onchocerciasis among children and in the community generally, (3) the ivermectin distribution process, and (4) the benefits or effects of taking ivermectin. Out of the 50 drawings, 30 were on symptoms, 7 on effects of the disease on children, 8 on distribution process, and 5 represented multiple perceptions on symptoms, drug distribution processes, benefits, and effects of treatment. The lack of clarity when treatment with ivermectin can be stopped in endemic areas requires working with children to ensure continued compliance with treatment into the future. Children's drawings should be incorporated into health education interventions.