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WHAT IS KNOWN AND OBJECTIVE Drug-drug interactions can involve inhibition or induction of cell membrane transporters. Deinduction occurs after an inducing agent is stopped. CASE SUMMARY This case describes suspected P-glycoprotein (P-gp) deinduction by carbamazepine resulting in a slow viral response during treatment of chronic hepatitis C virus (HCV) infection. Evidence of deinduction occurred beyond clearance of carbamazepine and resulted in extension of HCV treatment. WHAT IS NEW The understanding of the role P-gp transport plays in drug elimination is relatively new and evidence of P-gp deinduction is variable. CONCLUSION Clinicians should consider deinduction when starting and stopping medications involving strong inducers of P-gp transport proteins.

Adequate pharmacotherapy in critically ill patients is challenging for many clinicians. Disease-related pathophysiological changes often lead to complex therapy strategies including many intensive care treatments (e.g. invasive ventilation, renal replacement therapy). These measures often influence drug prescribing and dosing. Therefore, in organ dysfunction such as renal and liver impairment reduced drug elimination has to be considered by adapting drug dosing towards elimination rates. Moreover, as intensive care medicine often includes the use of multiple drugs the risk for drug-drug interactions increases. The current article gives an overview about the complexity of individual pharmacotherapy in intensive care units whilst providing information for its clinical implementation.

Drug elimination is the removal of active drug from the body. Metabolism takes place largely in the liver and produces water soluble metabolites which can be excreted in the bile or urine. Metabolism may also produce active or toxic metabolites or a pharmacologically active drug from an inactive prodrug. Most volatile anaesthetics are excreted unchanged via the lungs. Drug elimination can be affected by factors such as first-pass metabolism, genetic variants and various disease processes. Knowledge of these processes will allow better prediction of pharmacokinetics in practice.

Clearance is one of the most widely quoted and applied pharmacokinetic concepts in drug development and therapy. Its foundations and associated models of drug elimination are well embedded and accepted within the scientific community. Recently, however, the prevailing views that have held us in good stead for the past almost 50 years have been challenged with the argument that organ clearance should not be based on elimination rate, now defined by extraction across the liver divided by incoming or systemic concentration, as in current practice, but rather, by the mean concentration of drug within the blood in the organ, which is model-dependent. We argue that all needed parameters already exist, and that the proposed new approach to organ clearance is confusing and unnecessary. SIGNIFICANCE STATEMENT: Clearance concepts are widely applied in drug development and therapy. Historically, hepatic clearance has been defined as the ratio of rate of elimination divided by ingoing blood concentration. Recently, this approach has been challenged arguing that clearance should be referenced to blood concentration within the liver extrapolation (IVIVE). There is no need for additional, a feature that corresponds to intrinsic clearance of the chosen clearance model, a widely accepted parameter in physiologically based pharmacokinetic (PBPK) and in vitro to in vivo extrapolation (IVIVE). There is no need for additional, confusing clearance terms, which offer no material benefit.

Sulfamethoxazole-Trimethoprim residues in eggs can cause risks to human health. The most common cause of residues in eggs results from failure to meet an appropriate withdrawal interval. The aim of this study was to determine the quantity and duration of sulfamethoxazole-trimethoprim residues in eggs and evaluate the drug elimination parameters in egg components and whole egg to better estimate the withdrawal interval of sulfamethoxazole and trimethoprim following oral administration for 7 days at a purposed dosage regimen (time average 46 mg kg−1 day−1 for sulfamethoxazole, time average 25 mg kg−1 day−1 for trimethoprim). Residues of sulfamethoxazole and trimethoprim in albumen and yolk were analyzed by ultra-performance liquid chromatography mass spectrometry. A greater percentage of sulfamethoxazole was distributed into the albumen (91.53–96.74%) and a greater percentage of trimethoprim was distributed into yolk (63.92–77.36%) during treatment. The residues levels in whole egg declined below or reached the limit of quantification until 13 days for SMZ and TMP respectively. The withdrawal interval for SMZ and TMP were 43 days and 17 days respectively using the FDA tolerance method.

The applications described in Chap. 3 are related to topics in the biological field, such as drug elimination, prostate cancer-related diseases, population growth, and epidemiological disease caused by HIV and COVID-19. In this chapter some scientific projects are suggested that may be useful for the development of research using an interval type-2 fuzzy set.

Activated charcoal both reduces primary drug absorption and enhances drug elimination. However, the two mechanisms of action overlap and are indistinguishable from each other. In order to estimate the extend of enhanced elimination, we summarized the effect of activated charcoal on intravenously administered drugs, where reduced drug exposure can be attributed to enhanced elimination. We performed a meta-analysis of randomized controlled studies evaluating the effect of orally administered activated charcoal on the systemic exposure of intravenously administered drugs. We searched the bibliographic databases PubMed, Embase and Cochrane. Meta-regression analyses of selected physiochemical drug properties on the effect sizes of activated charcoal were performed. All but one of 21 included studies used multiple-dose activated charcoal (MDAC). MDAC reduced the median half-life of the intravenously administered study drugs by 45.7% (interquartile range: 15.3%-51.3%) and area under the concentration time curve by 47.0% (interquartile range: 36.4%-50.2%). MDAC significantly improved drug elimination across nine different intravenously administered drugs, but we were unable to identify factors allowing extrapolation to other drugs. The results offer a possible and plausible rationale for the previously observed effects of single-dose activated charcoal beyond the timeframe where ingested drug is present in the gastro-intestinal tract.

In reviewing previously published isolated perfused rat liver studies, we find no experimental data for high-clearance metabolized drugs that reasonably or unambiguously support preference for the dispersion and parallel-tube models versus the well-stirred model of organ elimination when only entering and exiting drug concentrations are available. It is likely that the investigators cited here may have been influenced by: 1) the unphysiologic aspects of the well-stirred model, which may have led them to undervalue the studies that directly test the various hepatic disposition models for high-clearance drugs (for which model differences are the greatest); 2) experimental assumptions made in the last century, which are no longer valid today, related to the predictability of in vivo outcomes from in vitro measures of drug elimination and the influence of albumin in hepatic drug uptake; and 3) a lack of critical review of previously reported experimental studies, resulting in inappropriate interpretation of the available experimental data. The number of papers investigating the theoretical aspects of the dispersion, parallel-tube, and well-stirred models of hepatic elimination greatly outnumber the papers that actually examine the experimental evidence available to substantiate these models. When all experimental studies that measure organ elimination using entering and exiting drug concentrations at steady state are critically reviewed, the simple but unphysiologic well-stirred model is the only model that can describe all trustworthy published available data. SIGNIFICANCE STATEMENT: Although the dispersion model of hepatic elimination more adequately reflects physiologic reality, there are no convincing experimental data that unambiguously favor this model. The well-stirred model can describe all well-designed perfusion studies with high-clearance drugs and nondrug substrates, but the field has not recognized this because of hesitation to accept a nonphysiologic model and flawed attempts to utilize in vitro-in vivo extrapolation approaches.

Purpose Clearance via renal replacement therapy (RRT) can significantly alter the pharmacokinetic profile of drugs. The aim of this study was (i) to improve the use of clinical trial data and (ii) to provide a model that allows quantification of all aspects of drug elimination via RRT including adsorption to dialysis membranes and/or degradation of the drug in the dialysate. Methods An integrated dialysis pharmacometric (IDP) model was developed to simultaneously incorporate all available RRT information. The sensitivity, accuracy and precision of the IDP model was compared to conventional approaches in clinical trial simulations and applied to clinical datasets of teicoplanin and doripenem. Results The IDP model was more accurate, precise and sensitive than conventional plasma-concentration-based approaches when estimating the clearanceRRT (relative bias

Background: Hospital wastewater (WWs) represents a particular type of effluent, compared with urban wastewater. Hospitals generate on average 750 L of wastewater by the bed and by day so they are 2-5 times higher than urban flow rates, which refer to one inhabitant equivalent (typically included in the interval 120-250 L). This significant quantity of water per day for different purposes and services depending on the activities which take place within the structure. Methods: In our work, we proposed tow methods; the first one is the complexation with CD for the treatment of drugs from Hospital WWs, which makes solid precipitate that can be filtered later. Our second method is the photodegradation of most drugs found in Hospital WWs with a know UV lamp and time for each type of drug elimination. Results: Our result for the first method is the formation of a CD-drug complex as a solid precipitate which will be filtered later and eliminate the solution to be purified. For the second method, the use of the UV lamp at 300 nm gave a degradation of 70% of the drug of the solution after 30 minutes of irradiation. The follow-up of the photodegradation was carried out by UV spectroscopy. Conclusion: The elimination of drugs from hospital waters is essential, the method we have developed on a small scale can be standardized in Algerian hospitals that do not contain hospital water treatment policies, before reaching urban waters. This congress will be the occasion to discuss this national problem and a call of installation of ministry at the level of each hospital.

Therapeutic antibodies administered intravitreally are the current standard of care to treat retinal diseases. The ocular half-life (t1/2) is a key determinant of the duration of target suppression. To support the development of novel, longer-acting drugs, a reliable determination of t1/2 is needed together with an improved understanding of the factors that influence it. A model-based meta-analysis was conducted in humans and nonclinical species (rat, rabbit, monkey, and pig) to determine consensus values for the ocular t1/2 of IgG antibodies and Fab fragments. Results from multiple literature and in-house pharmacokinetic studies are presented within a mechanistic framework that assumes diffusion-controlled drug elimination from the vitreous. Our analysis shows, both theoretically and experimentally, that the ocular t1/2 increases in direct proportion to the product of the hydrodynamic radius of the macromolecule (3.0 nm for Fab and 5.0 nm for IgG) and the square of the radius of the vitreous globe, which varies approximately 24-fold from the rat to the human. Interspecies differences in the proportionality factors are observed and discussed in mechanistic terms. In addition, mathematical formulae are presented that allow prediction of the ocular t1/2 for molecules of interest. The utility of these formulae is successfully demonstrated in case studies of aflibercept, brolucizumab, and PEGylated Fabs, where the predicted ocular t1/2 values are found to be in reasonable agreement with the experimental data available for these molecules.

Thorough exploration of alternative dosing frequencies is often not performed in conventional pharmacometrics approaches. Quantitative systems pharmacology (QSP) can provide novel insights into optimal dosing regimen and drug behaviors which could add a new dimension to the design of novel treatments. However, methods for such an approach are currently lacking. Recently, we illustrated the utility of frequency-domain response analysis (FdRA), an analytical method used in control engineering, using several generic pharmacokinetic-pharmacodynamic case studies. While FdRA is not applicable to models harboring ever increasing variables such as those describing tumor growth, studying such models in the frequency domain provides valuable insight into optimal dosing frequencies. Through the analysis of three distinct tumor growth models (cell cycle-specific, metronomic, and acquired resistance), we demonstrate the application of a simulation-based analysis in the frequency domain to optimize cancer treatments. We study the response of tumor growth to dosing frequencies while simultaneously examining treatment safety, and found for all three models that above a certain dosing frequency, tumor size is insensitive to an increase in dosing frequency, e.g., for the cell cycle-specific model, one dose per 3 days, and an hourly dose yield the same reduction of tumor size to 3% of the initial size after 1 year of treatment. Additionally, we explore the effect of drug elimination rate changes on the tumor growth response. In summary, we show that the frequency-domain view of three models of tumor growth dynamics can help in optimizing drug dosing regimen to improve treatment success. Electronic supplementary material The online version of this article (10.1208/s12248-019-0372-4) contains supplementary material, which is available to authorized users.

Multidrug resistance (MDR) to chemotherapy presents a major obstacle in the treatment of cancer patients, which directly affects the clinical success rate of cancer therapy. Current research aims to improve the efficiency of chemotherapy, whilst reducing toxicity to prolong the lives of cancer patients. As with good biocompatibility, high stability and drug release targeting properties, nanodrug delivery systems alter the mechanism by which drugs function to reverse MDR, via passive or active targeting, increasing drug accumulation in the tumor tissue or reducing drug elimination. Given the potential role of nanodrug delivery systems used in multidrug resistance, the present study summarizes the current knowledge on the properties of liposomes, lipid nanoparticles, polymeric micelles and mesoporous silica nanoparticles, together with their underlying mechanisms. The current review aims to provide a reliable basis and useful information for the development of new treatment strategies of multidrug resistance reversal using nanodrug delivery systems.

During the development, dosage optimization and safety evaluation of a drug, rapid and precise monitoring of administered drug and/or its metabolites in biological samples including blood, plasma, serum, tissues and saliva are vital. As drug biotransformation produces more hydrophilic metabolites for the enhancement of drug elimination, which is often a challenge for traditional reversed-phase liquid chromatography (RPLC) separation. Because hydrophilic interaction liquid chromatography (HILIC) is capable of retaining polar compounds and readily compatible with mass spectrometry (MS), HILIC has been used as a complementary separation technique to RPLC for analysis of polar metabolites, especially polar drugs and their metabolites. This review covers core aspects of HILIC-MS/MS method and overall profile of its application in analysis of drug and/or its metabolites. The emphasis of this paper has been placed on the applications of HILIC-MS/MS method in quantitative bioanalysis of drugs alone or along with their metabolites in drug metabolism studies in recent years. As a fundamental and critical step of bioanalytical method, conventional sample preparation techniques of biological matrices for the HILIC-MS/MS analysis of drugs and/or their metabolites are also briefly featured.

Objective Early diagnosis of malignant tumors is essential to successfully plan a radical and curative approach. In this study we describe the direct radiolabeling of doxorubicin (DOX) at physiological pH to identify murine breast tumor (4T1 cells)-bearing BALB/c mice. Materials and methods Technetium-99m (99mTc) DOX was prepared by adding 99mTc-pertechnetate to a PBS (pH 7.4) solution containing DOX in the presence of stannous chloride. Radiochemical purity and in-vitro stability were determined. The circulation time of 99mTc-DOX was determined by measuring blood radioactivity in healthy animals. Scintigraphic images and biodistribution studies were carried out in tumor-bearing mice at 1, 4, and 8 h after injection. Results The 99mTc-DOX complex showed high radiochemical purity (99.27 ± 0.34%) and in-vitro stability until 8 h. Tc-DOX levels in blood declined in a biphasic manner, with an α half-life of 4.5 min and a β half-life of 277.2 min. High uptake was achieved in kidneys, liver, and spleen, because of the drug elimination routes. Moreover, tumor uptake was higher than that of control tissue, resulting in high tumor-to-muscle ratios. Conclusion DOX was successfully labeled with 99mTc-pertechnetate and showed high stability. Biodistribution and scintigraphic studies indicated high tumor-to-muscle ratios in breast tumor-bearing BALB/c mice. These results suggested the feasibility of 99mTc-DOX as a functional agent in tumor diagnosis.

The members of the organic anion transporter (OAT) family are mainly expressed in kidney, liver, placenta, intestine, and brain. These transporters play important roles in the disposition of clinical drugs, pesticides, signaling molecules, heavy metal conjugates, components of phytomedicines, and toxins, and therefore critical for maintaining systemic homeostasis. Alterations in the expression and function of OATs contribute to the intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs, and to many pathophysiological conditions. Consequently, the activity of these transporters must be highly regulated to carry out their normal functions. This review will present an update on the recent advance in understanding the cellular and molecular mechanisms underlying the regulation of renal OATs, emphasizing on the post-translational modification (PTM), the crosstalk among these PTMs, and the remote sensing and signaling network of OATs. Such knowledge will provide significant insights into the roles of these transporters in health and disease.

ATP binding cassette (ABC) transporters play a pivotal role in drug elimination, particularly on several types of cancer in which these proteins are overexpressed. Due to their promiscuous ligand recognition, building computational models for substrate classification is quite challenging. This study evaluates the use of modified Self-Organizing Maps (SOM) for predicting drug resistance associated with P-gp, MPR1 and BCRP activity. Herein, we present a novel multi-labelled unsupervised classification model which combines a new clustering algorithm with SOM. It significantly improves the accuracy of substrates classification, catching up with traditional supervised machine learning algorithms. Results can be applied to predict the pharmacological profile of new drug candidates during the drug development process.

Chimeric antigen receptor (CAR) T-cell therapy has been clinically proven to efficiently combat haematological malignancies. However, continuous efforts are required to increase the specificity of CAR T-cells against tumour versus normal tissues, and are essential to improve their antitumour activity in solid tumours. This review summarises the structure of major CAR designs, and strategies to overcome immunosuppressive tumour microenvironment, and reduce toxicities. Along with reviewing currently available techniques that allow the elimination of CAR T-cells after they fulfil their desired functions, using suicide genes, drug elimination strategies are also introduced. A better understanding of the strengths and pitfalls of CAR T-cell therapy will provide fundamental knowledge for the improvement of engineered T-cell therapy in the near future.

The main purpose of a phase I dose-finding study in the field of oncology is to evaluate toxicity and pharmacokinetic (PK) data and to estimate the optimal dose (OD) for subsequent clinical trials. From a pharmacological perspective, PK information is considered as an appropriate indicator for evaluating the degree of drug intervention in humans. Dose proportionality is typically assessed to investigate the PK properties of a drug. If we rely solely on the dose-exposure relationship, then when this relationship is not proportional, eg, if there is saturation of drug elimination or absorption, the performance of OD selection may be affected. This may be because any exposure ratio between two dose levels differs from the dose ratio between the dose levels. In addition, large inter-individual variability in exposure affects the occurrence of toxicity. Therefore, incorporating PK assessment in a phase I dose-finding trial may enable us to more precisely estimate OD. In most oncology dose-finding clinical trials, however, the result of PK analysis is not explicitly incorporated in the dose-finding determination analysis. In this study, we propose a Bayesian approach to incorporating PK assessment into OD estimation in a dose-finding trial. Our proposed approach incorporates into the statistical model an adjustment based on the latest area under the time-concentration curve assessment. The simulation study shows that compared with standard methods, the proposed method may be better able to select the correct ODs across a variety of realistic settings.

A traditional focus of exercise scientists studying the interaction of drugs and exercise has been on the effects of drugs on exercise performance or functional capacity. In contrast, there is limited information available about the effects of exercise on the efficacy of drugs that have been prescribed and ingested for therapeutic reasons. Those requesting the approval for the manufacture, distribution, and sale of new drugs to the public are required to submit evidence of drug effectiveness and safety to drug regulatory bodies. But, there is no associated requirement to include among that evidence the interactions of exercise with drugs. However, the physiological adaptations to acute and chronic exercise are such that there is good reason to suspect that exercise has the potential to significantly influence drug absorption and bioavailability, drug distribution within the body, and drug elimination from the body. This paper reviews the potential for interaction between exercise and pharmacokinetics.

The intraocular administration of the ciliary neurotrophic factor (CNTF) has been found to attenuate the photoreceptor degeneration and preserve retinal functions in the animal research models of the inherited or induced retinal disease. Studies with the aim of CNTF transfer to the posterior segment inside the eye have been directed to determine the best method for its administration. An ideal delivery method would overcome the eye drug elimination mechanisms or barriers and provide the sustained release of the CNTF into retina in the safest fashion with the minimum harm to the quality of life. This review focuses on the present state of CNTF delivery to retina, also provides an overview of available technologies and their challenges.

Background Fish are vulnerable to stress from over-crowding during transportation and eugenol is the most common sedative used to minimize fish injury. The ADI value of 2.5 mg/kg is recommended by the Joint FAO/WHO Expert Committee on Food Additives. The aim of this work was to study the elimination kinetics of eugenol following exposure of grass carp to a eugenol bath in a simulated transportation setting. Results Grass carp, Ctenopharyngodon idella (120 fish) were exposed for 24 h to a 10 mg/L eugenol bath. Sampling was performed during a 96 h period after the 24 h bath. Eight fish were sampled at each time point and muscle, plasma and liver concentrations of the drug were determined by ultra-performance liquid chromatography-tandem mass spectrometry. The concentration-time data of eugenol in each tissue were analyzed using non-compartmental methods. The peak concentrations (Cmax) in plasma, muscle and liver were 7.68, 5.30 and 24.63 mg/kg and the elimination half-lives (t1/2β) were 19.79, 10.27 and 55.28 h, respectively. The clearance (CL) values were 0.10, 0.44 and 0.04 L/h/kg and the areas under the concentration-time curve (AUC0-96h) were 91.54, 22.44, and 214.12 mg·h/L in plasma, muscle and liver, respectively. After a eugenol exposure bath, drug concentrations in muscle tissue of grass carp were below 1 mg/kg at 8 h and 0.1 mg/kg at 24 h. Conclusions The drug concentrations in muscle tissue at 8 h were lower than the recommended ADI value.

Purpose: Many biologics exhibit target-mediated drug disposition (TMDD). That is, given the high affinity and low doses typical for antibody-based therapeutics, drug clearance is often mediated through target binding and endocytosis, in addition to 1st-order elimination processes. Accounting for the process of TMDD in pharmacokinetic (PK) models is thus necessary to describe and predict drug exposure. TMDD is typically characterized by dose-dependent clearance, wherein drug elimination is faster at lower doses. In standard TMDD-models, target concentration and turnover are assumed to be constant. While this is generally a good approximation, the assumption does not always hold. Immune-stimulating drugs are the largest class of agents currently being developed in oncology, including checkpoint inhibitors (PD-1/PD-L1, CTLA4), cytokines (IL-2, IL-15), and immune agonists (GITR, OX40, ICOS). For immune-stimulating agents, drug treatment may induce lymphocyte proliferation, expanding the pool of target along with the target-expressing cells. TMDD in such cases is thus induced by drug treatment, and thereby target burden is dynamic; both dose- and time- dependent. PK dose response profiles in such cases could exhibit very different characteristics from standard (static) TMDD. Methods: The goal of this work is to invest the role of target dynamics on drug pharmacokinetics (PK) and receptor occupancy (RO). To do so, we have developed a mathematical modelling construct termed ‘Drug-induced TMDD’, wherein drug-target binding induces increase of the target synthesis rate, subsequently target concentration, leading to enhanced TMDD. We incorporate this construct into a 2-compartment model typical of monoclonal antibodies. Simulations were then used to characterize how dose, drug-target affinity, and the amplitude and the delay in target up-regulation affect the PK and RO profiles, and compared static vs. drug-induced TMDD behavior. Results: For Drug-induced TMDD, target expression increases with increased target engagement. This creates a pseudo-negative-feedback circuit, wherein the rate of TMDD-mediated clearance is dependent upon drug concentration. As a result, drug clearance does not appear dose-proportional at low doses, as is typical of static-TMDD. The AUC of drug concentration for drug-induced TMDD can be higher than static TMDD at low doses, but lower at higher doses. Similar results are predicted for the AUC of RO as well with the nominal parameter set. Increasing target affinity (decreasing KD) however results in faster clearance, typical of both cases of TMDD. Conclusions: Dynamic-TMDD could lead to different dose-dependent PK and RO behaviors from a static TMDD. Based on these characteristic profiles presented, one can determine whether a static vs. drug-induced TMDD model may be required for PK modelling, particularly important consideration for immune-stimulating biologics. Citation Format: Fei Hua, David Flowers, Daniel C. Kirouac, John M. Burke, Joshua F. Apgar. Drug-induced TMDD: a novel class of PK models relevant to Immune-stimulating therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 678.

Background Alkalized hydration is used as supportive care to prevent renal toxicity during infusions with high-dose methotrexate (HDMTX). In children with acute lymphoblastic leukemia (ALL), the hydration is commonly initiated 4 hours before start of the methotrexate (MTX) infusion. To test if longer duration of prehydration would prevent MTX-induced renal toxicity, we preformed a randomized cross-over study comparing 12-4 hours of hydration before the infusion of HDMTX. Procedures Children with ALL and non-Hodgkin lymphoma that were treated with infusions of HDMTX 5 or 8 g/m(2) were randomized to receive intravenous prehydration 12 or 4 hours before the first HDMTX infusion. Patients alternated between 12 and 4 hours of prehydration in the subsequent HDMTX infusions. Renal toxicity was defined as 50% increase in plasma creatinine after the HDMTX infusion. The plasma MTX concentration was measured during and after the HDMTX infusion to determine if the duration of prehydration would influence the systemic MTX clearance. Results A total of 47 patients (224 HDMTX infusions) with a median age of 4.9 years were included in the study. The duration of prehydration had no effect on MTX induced renal toxicity that occurred in 18.5% of all HDMTX 5 g/m(2) infusions and in 40.0% of all HDMTX 8 g/m(2) infusions. Similar the duration of prehydration had no impact on the systemic clearance of MTX. Conclusion Extending prehydration beyond 4 hours does not reduce the risk of renal toxicity or delayed MTX clearance after infusions with HDMTX 5-8 g/m(2).

Paediatric dose cannot be scaled down directly from an adult using weight (eg, mg/kg). This results in a dose too small in infants and children because elimination does not change in direct proportion to weight, and a dose too large in neonates whose drug elimination pathways are immature. The goal of treatment is a desired response (the target effect). An understanding of the concentration-response relationship (pharmacodynamics) can be used to predict the target concentration required to achieve this target effect. Pharmacokinetic knowledge then determines the target dose that will achieve the target concentration. Variability associated with both pharmacokinetics and pharmacodynamics can be reduced by demographic information (covariates), which can be used to help predict the target dose in a specific child. The covariates of size, maturation and organ function are the three principle contributors to pharmacokinetic variability. Children (2 years postnatal age or older) are essentially similar to adults (ie, mature) and differ only in size. Maturation processes are only important in neonates and infants, therefore, this cohort can be viewed as immature children. Paediatric pharmacodynamic studies are fewer than pharmacokinetic studies, but are required to elucidate the target concentration and consequent dose. The lack of pharmacodynamic studies is a serious challenge for rational dosing.

Gastrotoxicity is a major problem for long-term therapy with non-steroidal anti-inflammatory drugs (NSAIDs). DICCIC (1-(2,6-dichlorophenyl)indolin-2-one) is a new diclofenac prodrug, which has proven anti-inflammatory activity without gastroulcerogenic effect. The aim of this work was to compare the pharmacokinetic profiles of diclofenac from DICCIC (7.6 mg/kg equivalent to 8.1 mg/kg diclofenac) and diclofenac (8.1 mg/kg) administration in Wistar rats weighing 250-300 g (n=20). The doses were calculated by interspecific allometric scaling based on the 2 mg/kg from diary human dose of diclofenac. Blood samples were collected in heparinized tubes via the femoral artery through the implanted catheter. The plasma was separated and quantitation was made in a HPLC system with a UV-Vis detector. The confidence limits of the bioanalytical method were appropriate for its application in a preclinical pharmacokinetic study. The AUC of diclofenac from DICCIC (53.7± 5.8 ug/mL.min) was significantly less (Mann Whitney test, p

In this chapter, the term “adverse drug event” (ADE), rather than “reaction,” is used to emphasize the occurrences that are usually multifactorial and often include both biologic and system issues. No drug is free of ADE risk, and prescription of a drug therefore requires the physician to estimate that the risks of therapy are outweighed by the benefits. The list of ADEs for any given drug, let alone for all drugs commonly used by one practitioner, is enormous, and so the problem of ADEs presents challenges not only in guiding prescriptions to maximize benefit and minimize risk but also in educating health practitioners in making such judgments in an increasingly complex molecular and genetic environment. Clearly, information tools play an increasing role in future drug prescribing. The chapter briefly explains the types of ADEs such as system errors, linking events to drug administration—the “easy” examples, linking events to drug administration—the “hard” examples, and many more. Furthermore, it also explains drug interactions that are especially likely to cause ADEs because they inhibit specific pathways for drug elimination. In this situation, ADEs are likely if a second “high-risk” drug using that pathway is also administered.

Most methods to estimate creatinine clearance (CCr) such as Cockroft–Gault (CG) and modification of diet in renal disease (MORD) use only a single sample of serum creatinine (SCr) on which to base their estimate. This only works when the patient is in a stable steady state. When renal function is changing and SCr is either rising or falling, SCr has not yet reached such a stable steady state. Because of this, the change in CCr estimated by methods using only a single SCr is always false and is always late in being recognized. What is needed is to estimate CCr from a pair of changing SCr samples. The one with most clinical use is described in this chapter. It uses a pair of SCr samples taken at known times, and calculates the CCr that makes SCr go from that initial value to the second one in the stated time period in a patient of the stated age, gender, height, and weight. When SCr is stable, its results are close to CG. When changing, it provides superior ability to track CCr in intensive care unit patients, for example. While such estimates may be biased due to systematic errors in estimation of creatinine production, the method nevertheless provides a direct link between the changes in a patient’s SCr the possibly biased estimate of glomerular filtration rate, whatever it may beand dry behaviour, with direct information of the relationship between SCr and drug elimination.

Background One of the major issues in current pharmaceutical development is potential hepatotoxicity and drug-induced liver damage. This is due to the unique metabolic processes performed in the liver to prevent accumulation of a wide range of chemicals in the blood. Recently, we developed a physiologically-based lattice model to address the transport and metabolism of drugs in the liver lobule (liver functional unit). Method In this paper, we extend our idealized model to consider structural and spatial variability in two and three dimensions. We introduce a hexagonal-based model with one input (portal vein) and six outputs (hepatic veins) to represent a typical liver lobule. To capture even more realistic structures, we implement a novel sequential diffusion-limited aggregation (DLA) method to construct a morphological sinusoid network in the lobule. A 3D model constructed with stacks of multiple 2D sinusoid realizations is explored to study the effects of 3D structural variations. The role of liver zonation on drug metabolism in the lobule is also addressed, based on flow-based predicted steady-state O2 profiles used as a zonation indicator. Results With this model, we analyze predicted drug concentration levels observed exiting the lobule with their detailed distribution inside the lobule, and compare with our earlier idealized models. In 2D, due to randomness of the sinusoidal structure, individual hepatic veins respond differently (i.e. at different times) to injected drug. In 3D, however, the variation of response to the injected drug is observed to be less extreme. Also, the production curves show more diffusive behavior in 3D than in 2D. Conclusion Although, the individual producing ports respond differently, the average lobule production summed over all hepatic veins is more diffuse. Thus the net effect of all these variations makes the overall response smoother. We also show that, in 3D, the effect of zonation on drug production characteristics appears quite small. Our new biophysical structural analysis of a physiologically-based 3D lobule can therefore form the basis for a quantitative assessment of liver function and performance both in health and disease Electronic supplementary material The online version of this article (doi:10.1186/s12976-016-0034-5) contains supplementary material, which is available to authorized users.

Liver modeling in pharmacokinetics has been based on outflow curves of extracellular tracers obtained in single-pass perfused rat livers. These reference curves represent the hepatic transit time densities (TTD) of tracers. Since the fractal structure of the sinusoidal network implies a TTD with power-law tail, the question is whether the use of conventional empirical TTDs with exponential tail may lead to biased estimates of hepatic clearance. A simulation study using a novel TTD model that accounts for fractal heterogeneity of hepatic flow shows that the bias is less than about 5%. Using this approach to determine the influence of hepatic flow dispersion on drug extraction, only a minor effect was found. The results demonstrate that there is no need for specific fractal models of hepatic drug elimination.

Current data about the role of adamantanes and neuraminidase inhibitors (NIs) in the chemoprophylaxis against influenza viruses were reviewed. We found significant evidence favouring the role of NIs in the chemoprophylaxis of influenza. Awareness and prudent use are necessary, due to recent evidence of gradually increasing resistance of several influenza strains to these agents. On the other hand, the role of adamantanes appears to have decreased over the last decade. Both pre-pandemic and the novel pandemic A/H1N1 2009 strains exhibited either increasing rates of resistance or no susceptibility to adamantanes. Adamantanes currently only have a theoretical role in influenza chemoprophylaxis given the likelihood of the occurrence of an epidemic due to a susceptible strain. In conclusion, changes in antiviral susceptibility will affect future guidance in prophylaxis against influenza. Further investigation of novel medications with new mechanisms of action is important in this regard. Meanwhile, implementing strategies to conserve our current antivirals is necessary. © 2012 Bentham Science Publishers. 19 35 5947 5956

This paper presents a three-dimensional (3D) tumor spheroid chip where the pharmacokinetic (PK) drug elimination model is developed by balanced droplet dispensing. The PK model should reflect the exponential decrease of drug concentration in a body to improve the reliability of cell-based screening assay. The previous cell chips, however, maintain the concentration of anti-cancer agents at constant or discretely decrease the concentration level by manual process. In the present chip where medium droplet dispensers are integrated on a well array, the small droplets of fresh medium and well waste are autonomously replaced each other, the exponential elimination of drug concentration in the well is provided. In the experimental study, we demonstrated that the present chip successfully develops the exponential elimination model using fluorescein isothiocyanate (FITC) and cisplatin. Although the exponential decay of cisplatin in the present chip did not show significant effect biologically due to the current protocol where 3 days of constant concentration pre-treatment is performed, we observed different growth pattern of H358 spheroids depending on peak concentration of 0, 1, 10, and 100 μM. The present chip has potential for analyzing the response of 3D tumor spheroids in the pharmacokinetically relevant drug elimination model for high-reliability spheroid-based drug screening chip.

PURPOSE: Conventional bioavailability testing of dosage forms based on plasma concentration-time graphs of two products in a two-period, crossover-design, is not applicable to topical treatment of intestinal segments. We introduce an isotope dual-label approach ((13)C- and (15)N(2)-urea) for colon drug delivery systems that can be performed in a one-day, non-invasive study-design.METHODS: Four healthy volunteers took an uncoated or a ColoPulse-capsule containing (13)C-urea and an uncoated capsule containing (15)N(2)-urea. In case of colon-release (13)C-urea is fermented and (13)C detected as breath (13)CO(2). Absorbed (13)C-urea and (15)N-urea are detected in urine.RESULTS: C and (15)N in urine released from uncoated capsules showed a ratio of 1.01 ± 0.06. The (13)C/(15)N-recovery ratio after intake of a ColoPulse-capsule was constant and lower >12 h post-dose (median 0.22, range 0.13-0.48). The (13)C/(15)N-ratio in a single urine sample at t ≥ 12 h predicted the 24 h non-fermented fraction (13)C of 3 h) release and a fermented fraction (13)C >54 %.CONCLUSIONS: Breath and urine (13)C and (15)N data describe the release-profile and local bioavailability of a colon delivery device. This allows non-invasive bioavailability studies for evaluation of colon-specific drug delivery systems without radioactive exposure and with increased power and strongly reduced costs.

KuKanich, B., Hubin, M. The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs. J. vet. Pharmacol. Therap. 33, 42–49. Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 μg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 μg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time (MRT) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.

Heparin (100 U/kg bodyweight) was administered as single i.v. injections, and heparin concentration in plasma determined by polybrene titration. Mean concentration half-life was 74.7 min in the normal group (n = 6), 118.6 min in the nephrectomized patients (n = 5), and 97.8 min in the other uraemic patients (n = 6). The differences between the mean values for the normals and for the 2 patient groups were statistically significant (p is less than 0.001 and p approximately 0.2 respectively). Mean anticoagulant half-life (based on thrombin clotting time) was 64.3, 75.8 and 62.7 min in the 3 groups. The differences between heparin concentration half-life and anticoagulant half-life in the 3 groups were statistically significant. These differences may be partly explained by a significant fall in heparin cofactor activity after injection of heparin. There was a strong positive individual correlation between heparin concentration half-life and anticoagulant half-life in the patients (r = 0.94), but not in the normal group (r = 0.31). There was a strong negative individual correlation between heparin tolerance and heparin concentration half-life in the patients (r = -0.84), but no correlation in the normal group. It is concluded that severely impaired renal function has a significant, but moderate influence on heparin elimination.

The kidney is a primary route of drug elimination; abnormal kidney function is predicted to alter the pharmacokinetics of agents metabolized and/or excreted predominantly through this route. The high prevalence of mental disorders associated with psychotropic drug use in individuals with deteriorating renal function suggests there is a need to investigate the effects of renal failure on psychotropic pharmacokinetics. The aim of this review is to provide a clinically accessible overview of the effect of chronic renal failure on the pharmacokinetics for each of the major classes of prescribed psychotropic agents.All English language articles published between 1977 and 2008 were searched through PubMed, using the following keywords: "renal," "kidney," "pharmacokinetics," "renal impairment," "renal insufficiency," and "renal failure." Each of these search words was cross-referenced with the non-proprietary name of each psychotropic agent. The manufacturer's product insert was also reviewed for some agents for updated dosing. Owing to the lack of adequately powered studies, an inclusive manner was used.Chronic renal failure variably affects the pharmacokinetic parameters of psychotropic drugs. A review of each psychotropic drug is provided, with an emphasis on the individual pharmacokinetic parameters and recommended dosing.The adjudication of safe and effective doses for any psychotropic agent needs to be individualized. Tactics including dosage adjustment, slow titration, and careful monitoring for serious adverse events should be incorporated into practice.

The use of pharmacotherapy in the elderly requires caution because of increasing with age drug sensitivity and risk of dangerous adverse effects. The process of ageing induce alteration in pharmacokinetics of drugs. Modifications affect practically each pharmacokinetic phase. Processes of distribution and, first of all, drug elimination are the most essential for clinical practice.

PEGylation, association of poly(ethylene glycol) (PEG) to drug molecules or drug-bearing particles, is one of the most promising techniques on the way to improve the pharmacokinetic features of a drug which, in turn, leads to pharmacodynamic improvements.The aim of this review is to describe PEGylation as a procedure for alteration of drug molecular structure with the main emphasis on its pharmacokinetic consequences.After a brief but concise overview of the history and chemistry of PEGylation, the boundary of this literature survey is confined to the findings and reports on the impact of PEGylation on biodistribution and bioelimination of therapeutic molecules.It is concluded, based on the whole body of the data in literature, that the main results of PEGylation on pharmacokinetic properties of the drug include prolongation of lifespan in circulation, alterations in drug elimination pathway(s) and changes in drug biodistribution profile, among others, which all are derived from the structural changes that occur in the drug molecule, mainly reversible attachment of a large polymeric moiety to parent drug.

Drug elimination is the irreversible removal of drug from the body. In order to discuss the process, it is necessary to understand how the body handles drugs with a description of hepatic, renal and pulmonary clearance, as well as some of the other less common routes of elimination. Knowledge of first-pass metabolism along with discussion of the various disease states affecting elimination processes will allow better prediction of pharmacokinetics in practice.

The pharmacokinetic profile of antibiotics used in critically ill patients during continuous haemofiltration is different both from healthy people and from stable patients on long-term dialysis. This article reviews the patient-related, drug-related and haemofiltration-related variables influencing drug elimination in this group of patients, and provides specific recommendations for antibiotic dosing for different classes of antibiotics. Loading doses do not need to be altered. Subsequent dose adjustment should be based on the estimated ultrafiltration capacity of the renal replacement technique and the degree of extracorporeal clearance. A table of recommended doses is provided.

It has been shown previously that it is impossible to measure the volume of distribution at steady state conclusively for a multicompartment system from an iv bolus dose only. The problem lies in deciding from which compartment elimination of the drug occurs in the compartmental model. In this paper a new modelling strategy is examined whereby the compartment of elimination may be identified uniquely for the case of two-compartment models. The two models examined predict different profiles in the absorption phase of an oral profile. An in vivo data set is provided that favours a peripheral elimination explanation of its observed pharmacokinetics, based on the 'goodness of fit'.

The exact role of transporters in the absorption, distribution, and excretion (ADE) of drugs is still being elucidated; however, current evidence suggests that their role in these processes may be significant. In this review, the role of transporters in the ADE, pharmacology, toxicology, and clinical drug-drug interactions (DDIs) of drugs will be discussed. The current biological tools to assess this role and practical perspectives for the utilization of knowledge about drug transporters to drug discovery and development will also be discussed. Currently, regulatory agencies are focusing on these potential transporter-mediated DDIs. Therefore, guidance and caution on the investigation of these DDIs will be given.

Because of the wide inter individual variability between patients and their marked differences in drug response, one of the major issues that arises is adapting the therapy in question to the particular patient. In hospital, it is possible to vary the conditions of intravenous (i.v.) drug delivery by means of short infusions repeated at certain intervals. In this study, review of this process has been presented, and a therapeutic method described. It essentially consists of two stages. The first concerns the time of the first infusion, and the course of drug elimination: from two analyses of the drug concentrations in the blood made at two different times, the pharmacokinetic parameters of the patient are determined. Stage 2 consists of repeated short infusions and the therapy is adapted to the particular patient by varying the conditions involved. Thus, either the amount of the dose based on the rate of infusion or the time interval between the repeated infusions are varied. In order to reach a general solution, master curves are built by using dimensionless numbers as co-ordinates, such as time expressed in terms of the half-life t0.5 of the drug, and the drug concentration at the peaks defined as a fraction of the first unchanged peak concentration.

Monoclonal antibodies (mAbs) complex pharmacokinetic (PK) properties including a nonlinear pharmacokinetics and a significant variation in individual PK process cannot be appropriately described by classic PK models, probably derived form a poor understanding of the complex elimination of mAbs. In this study, a novel PK model based on mAbs' complex drug elimination was established. Subsequently, this new model was used to fit bevacizumab plasma concentration data from PK rabbits, and the outcomes of model fitting were compared with those came from a fit with classic models. In addition, the variations existing in the parameters set in the new model were analyzed. As a result, this novel model reasonably described the single-dose PK profiles of bevacizumab in rabbits, and its fitting efficiency was greatly improved compared with those fitted with classic PK models in terms of the weighted residual sum of squares. Moreover, the variations existing in the new model's parameters CA(antibody) and K0 could reasonably explain the individual variations of bevacizumab's PK profiles. In conclusion, the novel model reasonably explained the elimination of bevacizumab, and exhibited a potential as a useful tool for the PK studies of bevacizumab and other mAbs in practice.

The following essay explores the decision to terminate a federally funded program, Drug Elimination Program (DEP), in public housing developments. This case study of one public house development incorporates qualitative and quantitative data derived from a program evaluation performed in year 2000. A feminist framework directs this research with findings suggesting that the DEP efforts had substantially decreased drug activity and crime in this research setting.

Leptomeningeal carcinomatosis is defined as malignant infiltration of the pia matter and arachnoid membrane. Leukaemias and lymphomas, lung, breast cancer and melanoma are the primary tumours commonly associated with leptomeningeal carcinomatosis. Diagnosis is based on compatible symptoms and signs, cytological evidence of malignancy in the cerebrospinal fluid, and neuroimaging studies. Treatment is largely palliative (median survival 2 - 4 months). Patients with lympomatous or leukaemic meningitis, chemosensitive tumours such as breast cancer, low tumour burden, minimal neurological deficits, good performance status and controllable systemic disease survive longer with occasional long-term responses. Available treatment options include focal radiation therapy to CNS sites of bulky, symptomatic or obstructive meningeal deposits, intrathecal cytotoxic therapy and systemic chemotherapy. No evidence of superiority of intrathecal treatment compared with best palliative care (including radiation therapy and systemic treatment) is available from clinical trials. Novel treatment approaches include intrathecal liposomal Ara-C, the development of new cytotoxic compounds, signal transduction inhibitors and monoclonal antibodies for intrathecal or systemic use. Until data from multi-centre randomised trials are available, rationalisation of therapy should be done by stratifying patients to prognostic groups. High-risk patients will only survive for a few weeks and are better managed with supportive measures, whereas low-risk patients justify vigorous cerebrospinal fluid-directed treatment combined with radiation therapy and systemic chemotherapy. © 2005 Ashley Publications Ltd. 6 7 1115 1125