Time Course Of Drug Concentration Research Articles

MATHEMATICAL SOLUTION OF A PHARMACOKINETIC MODEL WITH SIMULTANEOUS FIRST-ORDER AND HILL-TYPE ELIMINATION

Mathematical studies on pharmacokinetic models are essentially important for drug development and optimal dose design. Considering the interaction between drug molecules and their receptors, the elimination of drug molecules can exhibit Hill-type kinetics. In this paper, motivated by the recombinant human granulocyte colony-stimulating factor (G-CSF) and the transcendent Lambert <i>W</i> function, we have studied the mathematical solutions of a one-compartment nonlinear pharmacokinetic model with simultaneous first-order and Hill-type (<i>n</i> = 2) elimination for the case of intravenous bolus administration. By introducing three well-defined transcendental functions depending on three different scenarios, we have established the closedform precise solutions of time course of drug concentration, which is a method to calculate drug concentrations at any time point. As a result, we also have derived the explicit expressions of some key pharmacokinetic surrogates such as the elimination half-life <i>t</i>_1/2 and total drug exposure (i.e. area under the concentration curve (AUC)), which are found as dose-dependent. Finally, a case study of a G-CSF drug is quantitatively illustrated to delineate our theoretical results, including the elimination half-life and AUC for different dosages. Our findings can provide an effective guidance for drugs with simultaneous first-order and Hill-type (<i>n</i> = 2) elimination in clinical pharmacology

Statistical analysis of one-compartment pharmacokinetic models with drug adherence.

Pharmacokinetics is a scientific branch of pharmacology that describes the time course of drug concentration within a living organism and helps the scientific decision-making of potential drug candidates. However, the classical pharmacokinetic models with the eliminations of zero-order, first-order and saturated Michaelis-Menten processes, assume that patients perfectly follow drug regimens during drug treatment, and the significant factor of patients' drug adherence is not taken into account. In this study, therefore, considering the random change of dosage at the fixed dosing time interval, we reformulate the classical deterministic one-compartment pharmacokinetic models to the framework of stochastic, and analyze their qualitative properties including the expectation and variance of the drug concentration, existence of limit drug distribution, and the stochastic properties such as transience and recurrence. In addition, we carry out sensitivity analysis of drug adherence-related parameters to the key values like expectation and variance, especially for the impact on the lowest and highest steady state drug concentrations (i.e. the therapeutic window). Our findings can provide an important theoretical guidance for the variability of drug concentration and help the optimal design of medication regimens. Moreover, The developed models in this paper can support for the potential study of the impact of drug adherence on long-term treatment for chronic diseases like HIV, by integrating disease models and the stochastic PK models.

Uncertain pharmacokinetic model based on uncertain differential equation

Pharmacokinetics is the study of the time course of drug concentrations in body compartments. The majority of drugs are eliminated at first order kinetics with a nonconstant elimination rate due to spontaneous erratic variations in the metabolic processes and individual difference. Noting the paradox of stochastic pharmacokinetic models, this paper proposes an uncertain pharmacokinetic model for mono-compartmental drugs administered with intravenous administration based on uncertain differential equations. Uncertainty distributions, expected values and confidence intervals of the half-life and the area under the curve are provided. For this method to achieve its full potential, this paper derives moment estimations for unknown parameters in this uncertain pharmacokinetic model. Finally a numerical example and a real data analysis illustrate our methods.

Iontophoretic Mediated Intraarticular Delivery of Deformable Liposomes of Diclofenac Sodium.

Topical therapy is ineffective in the case of Musculoskeletal Disorders (MSD) as it is not able to maintain therapeutic levels of the drug in the affected joint due to its inability to surpass the dermal circulation and penetrate into deeper tissues. One of the approaches to enhance deep tissue penetration of drugs is to increase drug delivery much above the dermal clearance. The objective of the present work was to formulate negatively charged Deformable Liposomes (DL) of Diclofenac Sodium (DS) using biosurfactants and target the same to the synovial fluid by application of iontophoresis. Deformable liposomes loaded with diclofenac sodium were formulated and characterized for surface morphology, particle size distribution, zeta potential and entrapment efficiency. In vitro permeation of the diclofenac from aqueous solution, conventional liposomes, and deformable liposomes under iontophoresis was performed using Franz diffusion cells and compared to passive control. Intraarticular microdialysis was carried out to determine the time course of drug concentration in the synovial fluid at the knee-joint region of the hind limb in Sprague Dawley rats. The vesicles were found to display a high entrapment (> 60%) and possess a negative zeta potential lower than -30 mV. The size of the vesicles was varied from 112.41 ± 1.42 nm and 154.6 ± 3.22 nm, demonstrated good stability on the application of iontophoresis. The iontophoretic flux values for the DS aqueous solution, conventional liposomes and deformable liposomal formulation were found to be 7.55 ± 0.42, 16.75±1.77and 44.01 ± 3.47 μg/ cm2 h-1, respectively. Deformable liposomes were found to display an enhancement of 5.83 fold compared to passive control. Iontophoresis was found to enhance the availability of DS deformable liposomes (0.56 ± 0.08 μg.h/ml) in the synovial fluid by nearly 2-fold over passive delivery (0.29 ± 0.05 μg.h/ml). Results obtained indicate that iontophoretic mediated transport of deformable liposomes could improve the regional bioavailability of diclofenac sodium to the synovial joints, an efficient mode for treating MSD in the elderly.

Development of a user-friendly training software for pharmacokinetic concepts and models.

Although there are many commercially available training software programs for pharmacokinetics, they lack flexibility and convenience. In this study, we develop simulation software to facilitate pharmacokinetics education. General formulas for time courses of drug concentrations after single and multiple dosing were used to build source code that allows users to simulate situations tailored to their learning objectives. A mathematical relationship for a 1-compartment model was implemented in the form of differential equations. The concept of population pharmacokinetics was also taken into consideration for further applications. The source code was written using R. For the convenience of users, two types of software were developed: a web-based simulator and a standalone-type application. The application was built in the JAVA language. We used the JAVA/R Interface library and the ‘eval()’ method from JAVA for the R/JAVA interface. The final product has an input window that includes fields for parameter values, dosing regimen, and population pharmacokinetics options. When a simulation is performed, the resulting drug concentration time course is shown in the output window. The simulation results are obtained within 1 minute even if the population pharmacokinetics option is selected and many parameters are considered, and the user can therefore quickly learn a variety of situations. Such software is an excellent candidate for development as an open tool intended for wide use in Korea. Pharmacokinetics experts will be able to use this tool to teach various audiences, including undergraduates.

Unsupervised learning of pharmacokinetic responses

Pharmacokinetics (PK) is a branch of pharmacology dedicated to the study of the time course of drug concentrations, from absorption to excretion from the body. PK dynamic models are often based on homogeneous, multi-compartment assumptions, which allow to identify the PK parameters and further predict the time evolution of drug concentration for a given subject. One key characteristic of these time series is their high variability among patients, which may hamper their correct stratification. In the present work, we address this variability by estimating the PK parameters and simultaneously clustering the corresponding subjects using the time series. We propose an expectation maximization algorithm that clusters subjects based on their PK drug responses, in an unsupervised way, collapsing clusters that are closer than a given threshold. Experimental results show that the proposed algorithm converges fast and leads to meaningful results in synthetic and real scenarios.

Bridging the Gap Between In Vitro Dissolution and the Time Course of Ibuprofen-Mediating Pain Relief

In vitro–in vivo extrapolation techniques combined with physiologically based pharmacokinetic models represent a feasible approach to establishing links between critical quality attributes and the time course of drug concentrations in vivo. By further integrating the results with pharmacodynamic (PD) models, scientists can also explore the time course of drug effect. The aim of this study was to assess whether differences in dissolution rates would affect the onset, magnitude, and duration of the time course of ibuprofen-mediating pain relief. An integrated in vitro–in vivo extrapolation–physiologically based pharmacokinetic/PD model was used to simulate pharmacokinetic and PD profiles for ibuprofen free acid (IBU-H) and its salts. Two elements of the pharmacokinetic profile, the peak of exposure (Cmax) and the time to peak concentration (Tmax), were sensitive to dissolution rate, whereas only 1 element of the pharmacodynamic profile was affected, namely the onset of drug action. The Cmax differences between IBU-H and its salts seem to be mitigated in the (hypothetical) effect compartment because of the concurrent distribution and elimination processes. Furthermore, the predicted maximum concentration in the effect compartment exceeded the EC80 value, which marks the plateau phase of the PD concentration–response curve, regardless of whether IBU-H or its salts were administered. Understanding the target site distribution kinetics and the potential nonlinearities between exposure and response will assist in setting criteria that are more scientifically based for the demonstration of therapeutic equivalence.

An Exploratory Microdialysis Study to Assess the Ocular Pharmacokinetics of Ciprofloxacin Eye Drops in Rabbits.

Despite the high frequency of use, data regarding the ocular in vivo pharmacokinetics (PK) of topically applied antibiotics are sparse. This study seeks to investigate the PK of the widely used fluoroquinolone ciprofloxacin by means of in vivo microdialysis. Twelve New Zealand white rabbits were included in the experiments. Under general anesthesia, microdialysis probes were implanted in the anterior chamber and the posterior segment of the same eye. After a period of 90 min after implantation, one drop of ciprofloxacin was administered onto the ocular surface. Microdialysis samples of the anterior chamber and the vitreous were collected every 30 min for 6 h. Relative recovery was assessed by retrodialysis to calculate absolute concentration values. Samples were analyzed using HPLC. In the anterior chamber, the maximum total drug concentration (Cmax) amounted to 0.373 ± 0.281 μg/mL and was reached (Tmax) after 116 ± 36 min. Calculated area under the concentration-time curve AUC(0-n) for ciprofloxacin in the anterior chamber was 78.8 ± 47.1 μg min/mL. For the vitreous, Cmax was 0.02 ± 0.03 μg/mL and maximum drug concentration was reached 107 ± 60 min after topical administration. AUC(0-n) for ciprofloxacin in the vitreous was 0.269 ± 0.370 μg min/mL. Microdialysis is a suitable method to assess in vivo pharmacokinetic profiles in the anterior chamber and in the vitreous. In the anterior chamber, maximum drug concentration was reached ∼2 h after single drug administration. Although the drug concentration in the vitreous was considerably lower, time course of drug concentration was comparable.

In‐vivo microdialysis as a new technique to assess ocular pharmacokinetics of topically applied drugs in a rabbit model

PurposeAlthough topical drug delivery is the most widely used ocular drug administration route, the in‐vivo pharmacokinetic profile of topically applied drugs is only inadequately described. This is mainly caused by the fact that in the eye the assessment of in‐vivo pharmacokinetics is difficult and technically demanding. Here, we propose a new technique for the in‐vivo assessment of pharmacokinetic parameters of topically applied drugs using in‐vivo microdialysis in a rabbit model.Methods8 Female New Zealand White rabbits were included in the experiments. A linear microdialysis probe (30 kDa molecular weight cut off [MWCO]) was implanted in the anterior chamber, a concentric probe (20 kDa MWCO) in the posterior segment of the same eye. After a run‐in period to obtain stabile conditions, a single drop of ciprofloxacin eye drops was administered on the cornea. Microdialysis samples were collected every 30 min for 6 h. Probes were analyzed using HPCL.ResultsIn the anterior chamber, the maximum total drug concentration was reached after 116 ± 36 minutes (Tmax) and amounted to 0.373 ± 0.281 μg/ml (Cmax). AUC (0‐n) for ciprofloxacin in the anterior chamber was 78.8 ± 47 μg min/ml. In the vitreous, drug concentration was considerably lower. A Cmax of 0.02 ± 0.03 μg/ml was reached after 106 ± 60 min. AUC (0‐n) for ciprofloxacin in the vitreous was 0.286 ± 370 μg min/ml.ConclusionsHere, we present in‐vivo microdialysis as a new method for the in‐vivo assessment of pharmacokinetic profiles. Maximum drug concentration in the anterior chamber was reached approximately 2 hours after single drug administration. Although the drug concentration in the vitreous was considerably lower, time course of drug concentration was comparable. In summary, our data show that microdialysis is an excellent method to assess in‐vivo pharmacokinetics with a high temporal resolution.

Effectiveness of saliva and fingerprints as alternative specimens to urine and blood in forensic drug testing.

In forensic drug testing, it is important to immediately take biological specimens from suspects and victims to prove their drug intake. We evaluated the effectiveness of saliva and fingerprints as alternative specimens to urine and blood in terms of ease of sampling, drug detection sensitivity, and drug detection periods for each specimen type. After four commercially available pharmaceutical products were administered to healthy subjects, each in a single dose, their urine, blood, saliva, and fingerprints were taken at predetermined sampling times over approximately four weeks. Fourteen analytes (the administered drugs and their main metabolites) were extracted from each specimen using simple pretreatments, such as dilution and deproteinization, and were analyzed using liquid chromatography/mass spectrometry (LC/MS). Most of the analytes were detected in saliva and fingerprints, as well as in urine and blood. The time-courses of drug concentrations were similar between urine and fingerprints, and between blood and saliva. Compared to the other compounds, the acidic compounds, for example ibuprofen, acetylsalicylic acid, were more difficult to detect in all specimens. Acetaminophen, dihydrocodeine, and methylephedrine were detected in fingerprints at later sampling times than in urine. However, a relationship between the drug structures and their detection periods in each specimen was not found. Saliva and fingerprints could be easily sampled on site without using special techniques or facilities. In addition, fingerprints could be immediately analyzed after simple and rapid treatment. In cases where it would be difficult to immediately obtain urine and blood, saliva and fingerprints could be effective alternative specimens for drug testing. Copyright © 2015 John Wiley & Sons, Ltd.

The role of quantitative ADME proteomics to support construction of physiologically based pharmacokinetic models for use in small molecule drug development.

Pharmacokinetics (PK) refers to the time course of drug concentrations in the body and since knowledge of PK aids understanding of drug efficacy and safety, numerous PK studies are performed in animals and humans during the drug development process. In vitro to in vivo extrapolation and physiologically based pharmacokinetic (PBPK) modeling are tools that integrate data from various in silico, in vitro, and in vivo sources to deliver mechanistic quantitative simulations of in vivo PK. PBPK models are used to predict human PK and to evaluate the effects of intrinsic factors such as organ dysfunction, age, and genetics as well as extrinsic factors such as co-administered drugs. In recent years, the use of PBPK within the industry has greatly increased. However, insufficient data on how the abundance of metabolic enzymes and membrane transporters vary in different human patient populations and in different species has been a limitation. A major advance is therefore expected through reliable quantification of the abundance of these proteins in tissues. This review describes the role of PBPK modeling in drug discovery and development, outlines the assumptions involved in integrating protein abundance data, and describes the advances made and expected in determining abundance of relevant proteins through mass spectrometric techniques.

PKPD modelling of the interrelationship between mean arterial BP, cardiac output and total peripheral resistance in conscious rats

The homeostatic control of arterial BP is well understood with changes in BP resulting from changes in cardiac output (CO) and/or total peripheral resistance (TPR). A mechanism-based and quantitative analysis of drug effects on this interrelationship could provide a basis for the prediction of drug effects on BP. Hence, we aimed to develop a mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model in rats that could be used to characterize the effects of cardiovascular drugs with different mechanisms of action (MoA) on the interrelationship between BP, CO and TPR. The cardiovascular effects of six drugs with diverse MoA, (amlodipine, fasudil, enalapril, propranolol, hydrochlorothiazide and prazosin) were characterized in spontaneously hypertensive rats. The rats were chronically instrumented with ascending aortic flow probes and/or aortic catheters/radiotransmitters for continuous recording of CO and/or BP. Data were analysed in conjunction with independent information on the time course of drug concentration using a mechanism-based PKPD modelling approach. By simultaneous analysis of the effects of six different compounds, the dynamics of the interrelationship between BP, CO and TPR were quantified. System-specific parameters could be distinguished from drug-specific parameters indicating that the model developed is drug-independent. A system-specific model characterizing the interrelationship between BP, CO and TPR was obtained, which can be used to quantify and predict the cardiovascular effects of a drug and to elucidate the MoA for novel compounds. Ultimately, the proposed PKPD model could be used to predict the effects of a particular drug on BP in humans based on preclinical data.

Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study

BackgroundIn the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180–185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.Methods/DesignMulticenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.DiscussionOn basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references.Trial registrationNTR2529.

My child is unique; the pharmacokinetics are universal

The pharmacokinetic (PK) parameters that are important for dosing (e.g., clearance and volume) are well known. They are used in universal mathematical formulae that describe the time course of drug concentration. Additional formulae can be used to describe major covariate effects in children, such as size and maturation. PK parameters describing the time-concentration profile of a drug after administration are those for a typical individual in a population. These parameters are associated with variability. Further, any one individual may not be typical of the population studied. While size and maturation are two important considerations in children and assist with dosing estimation, there are also a number of additional PK covariates (e.g., organ function, disease, drug interactions, pharmacogenetics), and identifying these sources of variability allows us to individualize drug dose. Pharmacology is not simply an application of PK, and determinants of drug dose also require an understanding of the variability associated with pharmacodynamic response and a balancing of beneficial effects against unwanted effects. Each child is unique in this respect.

Pharmacokinetic Concepts Revisited - Basic and Applied

Pathophysiological changes are common in critically ill patients, and can alter the time course of drug concentrations following dosing. The latter is termed pharmacokinetics (PK), and describes the relationship between dose administered and drug concentrations in plasma. Thus, modifications in PK necessitate dose adjustment, to optimize drug therapy in critical care. An understanding of basic PK principles is therefore required, to improve dosage guidelines in the population treated. Here, we define the key PK parameters, with specific application to critically ill patients. We then overview the methods used for PK analysis, in both research and in the clinical setting. Traditionally, non-compartmental and standard two-stage approaches have been used in small groups of patients with similar demographics and pathophysiology. However, these methods require intensive sampling, and do not explicitly describe inter-individual variability, or errors associated with measurement or sampling. Population PK (POPPK) modelling is advantageous in this regard, and can use both sparse and rich datasets to provide accurate estimates for between-subject variability (BSV). In addition, POPPK can explore patient parameter-covariate relationships, to account for some of the BSV in PK. This information is useful with assisting individualized dosing in the clinic. While the above methods are suitable for research, they are too time-consuming in the clinical setting, and Bayesian approaches have been adopted to optimize dosing. These methods, together with POPPK and appropriate study design are recommended for improved dosing in critical care.

One‐step method for plasma determination of ibuprofen by chemiluminescence‐coupled ultrafiltration and application in a pharmacokinetic study

A simple one-step method is established for plasma determination of ibuprofen and its pharmacokinetic study. The method involves simple sample pre-treatment by dilution, rapid separation by ultrafiltration (UF) and online sensitive detection by chemiluminescence (CL) based on significant intensity enhancement of ibuprofen on the weak CL of potassium permanganate and sodium sulphite in an acidic system. The calibration curve for ibuprofen is linear in the range 0.1-50.0 µg/mL in rat plasma. Average recoveries of ibuprofen at 0.80, 12.0 and 40.0 µg/mL amounted to 98.0 ± 4.2%, 101.2 ± 3.6% and 99.3 ± 5.4%, respectively. Standard deviations of intra- and inter-day measurement precision and accuracy are within ±10.0%. The detection limit for ibuprofen is 10.0 µg/L in plasma samples. Pharmacokinetic study of ibuprofen by the validated method shows that the mean plasma drug concentration-time course confirms to a classical two-compartment open model with first-order absorption. The proposed method will be an alternative for pre-clinical pharmacokinetic study of ibuprofen and other non-steroidal anti-inflammatory drugs.

The Øie–Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior

Introduction: Drug distribution is a major pharmacokinetic process that affects the time course of drug concentrations in tissues, biological fluids and the resulting pharmacological activities. Drug distribution may follow different pathways and patterns, and is governed by the drug's physicochemical properties and the body's physiology. The classical Øie–Tozer model is frequently used for predicting volume of drug distribution and for pharmacokinetic calculations.Areas covered: In this review, the suitability of the Øie–Tozer model for drugs that exhibit different distribution patterns is critically analyzed and illustrated. The method used is a pharmacokinetic modeling and simulation approach. It is demonstrated that the major limitation of the Øie–Tozer model stems from its focus on the total drug concentrations and not on the active (unbound) concentrations. Moreover, the Øie–Tozer model may be inappropriate for drugs with nonlinear or complex pharmacokinetic behavior, such as biopharmaceuticals, drug conjugates or for drugs incorporated into drug delivery systems. Distribution mechanisms and alternative distribution models for these drugs are discussed.Expert opinion: The Øie–Tozer model can serve for predicting unbound volume of drug distribution for 'classical' small molecular mass drugs with linear pharmacokinetics. However, more detailed mechanism-based distribution models should be used in preclinical and clinical settings for drugs that exhibit more complex pharmacokinetic behavior.

Study of the effective dose of a topical antifungal agent, omoconazole nitrate, on the basis of percutaneous pharmacokinetics in guinea-pigs and mice.

The clinically useful optimum dose of omoconazole nitrate, a topical antifungal agent, has been examined by analysing the percutaneous pharmacokinetics of the drug to assess its pharmacological activity in an in-vivo study. Creams containing omoconazole nitrate were prepared on a pilot basis. The therapeutic effect of the omoconazole nitrate creams was examined in an in-vivo pharmacological dermatophytosis infection model in guinea-pigs. Creams containing 0.25% or higher concentrations of omoconazole nitrate resulted in significant inhibition compared with no treatment and with vehicle-treated controls. In the mycological examination no growth of dermatophytes was observed for creams containing 1% or higher concentrations. In an in-vitro hairless mouse skin-permeability test a non-linear least squares program based on a fast inverse Laplace transform algorithm was used to calculate the partition and diffusion parameters of omoconazole nitrate in the stratum corneum and viable epidermis. The time-course of drug concentrations in the skin of the guinea-pig, estimated on the basis of these parameters, led to predictions that percutaneous drug concentrations on the guinea-pig would require 10 or more days to reach equilibrium in the skin; that drug concentrations in the corneum-viable epidermis border, where dermatophytes are considered to grow, would exceed the minimum effective concentration when 0.1% higher concentration creams were used; and that for binding to keratin drug concentrations would reach the practical minimum effective concentration when creams containing 0.5% or more omoconazole nitrate were used. These results show that partition and diffusion parameters obtained from in-vitro skin permeation studies can be used to predict in-vivo percutaneous pharmacokinetics and to estimate therapeutically effective concentrations.

Quantitative structure–pharmacokinetic relationships

Importance of the field: Quantitative structure–pharmacokinetic relationships (QSPKR) modeling is a valuable tool in drug discovery and development. It can provide insights into the molecular determinants of processes governing the time course of drug exposure and response.Areas covered in this review: Empirical and mechanism-based QSPKR models are discussed, including specific examples for oral absorption, nonspecific protein binding, volume of distribution, total metabolic stability and specific interactions with drug metabolizing enzymes. Emphasis is placed on state-of-the-art techniques, including new approaches for the direct simulation of concentration–time profiles from molecular descriptors (temporal QSPKR).What the reader will gain: Reviewing the application of current QSPKR modeling techniques will place these methods in context and highlight their respective advantages and limitations, as well as opportunities for further refinement.Take home message: The expansion of readily available molecular descriptors and advanced algorithms has improved empirical models and enabled the development of robust models for non-congeneric series. Empirical models focus on point estimates of global PK processes and physiologically-based models may be more desirable than data-driven methods. Further integration of relevant biological and pharmacological mechanisms will improve the ability to predict the full time course of drug concentration and effect profiles for diverse compounds and experimental conditions.

“ChilDrive”: A Technique of Combining Regional Cutaneous Hypothermia with Iontophoresis for the Delivery of Drugs to Synovial Fluid

Bioavailability of drugs in the synovial fluid when administered via transdermal route is highly limited due to the dermal clearance. The purpose of this project was to assess the efficiency of ChilDrive (CD) technique to improve the drug targeting to the synovial fluid. CD is a technique of transdermal delivery of drugs combining regional hypothermia and iontophoresis. Diclofenac sodium and Prednisolone sodium phosphate were administered by transdermal route (Passive, Iontophoresis, Chil-Passive and ChilDrive) at the knee-joint region of hind limb in sprague dawley rats for 6 h. Intraarticular microdialysis was carried out to determine the time course of drug concentration in the synovial fluid. Drug levels in synovial fluid after intravenous and intraarticular administration were also determined. Iontophoretic delivery increased the AUC(0-t) (area under the curve) of drugs in the synovial fluid by 3-fold over passive delivery (0.86 +/- 0.04 and 2.0 +/- 0.06 microg.h/ml for diclofenac sodium and prednisolone sodium phosphate, respectively). CD resulted in an AUC(0-t) of 5.2 +/- 0.69 and 24.6 +/- 1.97 microg.h/ml for diclofenac sodium and prednisolone sodium phosphate which was approximately 6-12-fold higher than the passive and 2-4-fold higher than iontophoresis. The results support our hypothesis that CD improves bioavailability of drugs to the synovial joints. CD could be developed as a potential noninvasive technique for treatment of arthritis.