Current Pharmaceutical Biotechnology - Volume 12, Issue 12, 2011

Full text available.

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.

Intensive care medicine deals with the critically ill; these patients usually have multiple organ failure, and complex medical conditions. The mortality in Australia and New Zealand among this population is approximately 16.1%, with approximately 24.2% having existing co-morbidities, and 23.4% of these patients experiencing sepsis or septic shock. Sepsis is a clinical syndrome that traditionally was regarded as a physiological maladaptive response to a foreign pathogen and ranges in disease severity from simple sepsis to septic shock, a life threatening condition, associated with multiple organ failure. Sepsis has profound effects on all systems of the body, and most notably the cardiovascular, renal and hepatic systems. There has been much research into the septic critically ill patient and recent developments in basic pharmacology and physiology has yielded results applicable to clinical practice. Sepsis may induce a state of increased cardiac output, which has significant effects on drug pharmacokinetics and pharmacodynamics. This increased cardiac output increases both renal and hepatic blood flow, and alters rates of antibiotic metabolism, and excretion. There are also alterations in the fluid compartments of the septic critically ill, that results in an altered volume of distribution, and ultimately decreased antibiotic concentrations at their site of action. This article will examine and review in detail the septic critically ill patient, and the effects that sepsis has on physiology and the resulting altered antibiotic pharmacokinetics and pharmacodynamics. Current knowledge suggests that the medical prescriber should be weary of antibiotic dosing in the septic critically ill, and consider alternative dosing regimes that are individualized to the patient in order to maximize efficacy.

Despite the importance of early an appropriate therapy for the outcomes of severe infections in critically ill patients, there is still little understanding of dose optimization during the most important phase of the treatment, the initial phase. Disease-driven variations in pharmacokinetics and pharmacokinetics/ pharmacodynamics may compromise the therapeutic success of antibiotic therapy. Therefore, dose adjustments that account for these variations are paramount for improving antibiotic use in critically ill patients. Compelling evidence shows significant increases in the Vd of both hydrophilic and lipophilic drugs in critically ill patients as a consequence of patient pathology and from clinical interventions. These increases in the Vd can lead to lower than expected plasma concentrations during the first day of therapy, which may result in sub-optimal achievement of antibiotic pharmacokinetics/pharmacodynamic targets, resulting in inappropriate treatment. Therefore, loading doses of antibiotic during the first day of therapy that account for the predicted increase in the Vd are required. Further research towards the establishment of new dosing regimens that use loading doses to satisfy such increased volumes of distribution is recommended.

To maximise the effect of an antibiotic it is necessary to pay careful attention to dosing. The maintenance dose is determined by antibiotic clearance which is usually determined in young healthy adults with normal physiology. Antibiotic clearance in critically ill patients may increase or decrease due to altered physiology and the treatments that are administered. Clearance may also vary significantly over time in patients with critical illness. Advancing age and comorbidities, in particular chronic kidney disease, can also decrease antibiotic clearance. Therefore, it is complicated and arguably impossible to suggest generic guidelines for the dosing of antibiotics in critically ill patients. Factors that influence clearance must be identified and accounted for in each patient for a rational approach to dose adjustment of antibiotics in patients with critical illness. The necessary changes can be predicted by understanding pharmacokinetic concepts. It is necessary to quantify organ function in patients at multiple time points because this can be used to estimate antibiotic clearance and guide dose selection. For example, creatinine clearance should be calculated but methods used in ambulatory patients may not apply to patients with critical illness. If possible, therapeutic drug monitoring should be conducted to ensure that antibiotic concentration targets are achieved and also to guide titration of subsequent doses. If blood sampling is carefully planned it may be possible to directly measure antibiotic clearance for dose adjustment. The purpose of this article is to review the concept of clearance and to highlight circumstances where antibiotic clearance may be altered in patients with critical illness. Strategies for dose modification of antibiotics in critically ill patients will be discussed.

On September 11, 1945 Maria Schafstaat was the first patient who successfully underwent a dialysis treatment for acute kidney injury (AKI), formerly known as acute renal failure. Since then, the number of patients with AKI is increasing worldwide. Today AKI is generally one feature of a multiple organ dysfunction syndrome (MODS), which develops in response to major surgery, cardiogenic shock or sepsis. Several clinical studies have shown that early and appropriate antibiotic therapy in those patients is of utter importance, yet it remains one of the most difficult challenges to meet. Even in critically ill patients with conserved renal function a myriad of pathophysiological changes, resulting in increased volume of distribution, decreased protein binding and altered hepatic drug clearance, makes appropriate antibiotic dosin difficult. Adequate pharmacotherapy, i.e. dose of anti-infective agens is becoming even more complicated if it has to be tailored to counteract their removal by different modes and intensities of renal replacement therapy. This review summarizes our sparse knowledge about pharmacokinetic studies and dosing recommendations of drugs in patients with AKI undergoing continuous renal replacement therapies (CRRTs) such as continuous venovenous hemofiltration (CVVH) as well as extended dialysis (ED), an increasingly used method to treat patients with AKI in the intensive care setting. We reflect on failure of several large prospective controlled studies to show a survival benefit of higher doses of renal replacement therapy, a finding that might be caused by the fact that we still adhere to dosing guidelines for antibiotics which are at best ineffectual but might also lead to potentially dangerous underdosing of these life saving drugs. Lastly we address possible strategies to overcome the lack of knowledge, the lack of data and the lack of interest in this important area of critical care medicine. Improvement of clinical outcomes and reduction of antibiotic resistance in this patient population will require nephrologist, intensivists and pharmacists to work together.

In-hospital and intensive care unit mortality rates for sepsis remain un-acceptably high, and have prompted the publication of international guidelines on best practice. Crucial to this is the application of early appropriate antibacterial therapy, in the correct dose. However, antibacterial regimes in this setting have largely been extrapolated from those in healthy volunteers, and fail to consider the unique pathophysiology and treatment provided to this population. As such, augmented renal clearance (ARC) - the enhanced renal elimination of circulating solute - is likely to be one of the more common physiological changes encountered in this setting, although to date remains largely under-appreciated. Significantly this may alter the pharmacokinetics of many routinely prescribed agents in this setting, pre-disposing to subtherapeutic levels or treatment failure. This review paper examines this phenomenon in detail, providing a summary of the likely underlying mechanisms, those patients at greatest risk, and the implications for antibacterial dosing in the critically ill.

The complexity of managing critically ill patients has increased since the early establishment of intensive care units in the 1950s. Despite of the fact that the number of drugs available to clinicians has increased, the understanding of the pharmacokinetics of individual drugs in specific disease states is still a matter of concern. Among the pharmacokinetic processes which may be affected in this patient population, drug distribution is a very important one. Changes in drug distribution may cause inadequate drug exposure at the infection site and consequently influence clinical outcome. Since drug distribution is dependent on a plethora of factors, including the physicochemical characteristics of the drug, we will focus on the most common mechanisms responsible for altered tissue distribution. These include changes in protein binding, fluid shifts, and pH changes. Although less common, alterations in organ perfusion may also play a role, particularly in heart failure patients. Despite great advances in understanding the distribution of antibacterial drugs, further studies are needed to define the consequences of changed drug distribution in critically ill patients on dosing regimens and clinical outcome.

There is pressing need to better understand pharmacokinetics in critically ill patients. This will aid clinicians in selecting optimal dosing regimens. Pharmacokinetic studies are difficult in this population due to the heterogeneity of the patients and the practical issues of research involving critically ill patients. Therapeutic drug monitoring is routinely performed to guide dosing for aminoglycoside and glycopeptide antibiotics. Expanding its use to other drug classes could provide new therapeutic advantages. Plasma concentration may not always reflect tissue distribution in critically ill patients. Microdialysis is a technique that can be applied in the Intensive Care Unit to measure tissue concentrations and provide further insights to antimicrobial therapy for critically ill patients. Finally, the application of population pharmacokinetic analysis in studies in critically ill patients may identify factors affecting pharmacokinetics and enhance drug dosing regimens for varied patient groups.

Efficacious therapy is of utmost importance to save lives and prevent bacterial resistance in critically ill patients. This review summarizes pharmacokinetic (PK) and pharmacodynamic (PD) modeling methods to optimize clinical care of critically ill patients in empiric and individualized therapy. While these methods apply to all therapeutic areas, we focus on antibiotics to highlight important applications, as emergence of resistance is a significant problem. Nonparametric and parametric population PK modeling, multiple-model dosage design, Monte Carlo simulations, and Bayesian adaptive feedback control are the methods of choice to optimize therapy. Population PK can estimate between patient variability and account for potentially increased clearances and large volumes of distribution in critically ill patients. Once patient- specific PK data become available, target concentration intervention and adaptive feedback control algorithms can most precisely achieve target goals such as clinical cure of an infection or resistance prevention in stable and unstable patients with rapidly changing PK parameters. Many bacterial resistance mechanisms cause PK/PD targets for resistance prevention to be usually several-fold higher than targets for near-maximal killing. In vitro infection models such as the hollow fiber and one-compartment infection models allow one to study antibiotic-induced bacterial killing and emergence of resistance of mono- and combination therapies over clinically relevant treatment durations. Mechanism-based (and empirical) PK/PD modeling can incorporate effects of the immune system and allow one to design innovative dosage regimens and prospective validation studies. Mechanism-based modeling holds great promise to optimize mono- and combination therapy of anti-infectives and drugs from other therapeutic areas for critically ill patients.

Bacteria becoming resistant to an increasing number of antibiotic classes are a major problem at hospitals including critical care units worldwide. Awareness of this problem and the need to prevent the development of antibiotic resistance are very important, especially since very few new antibiotics will become available in the near future. This article gives an overview of the mechanisms of antibacterial resistance and actual resistance data worldwide of the most prevalent Gram positive (MRSA, VISA/VRSE and VRE) and Gram negative bacteria (Pseudomonas aeruginosa, Acinetobacter spp., ESBL producing Enterobacteriaceae and Stenotrophomonas maltophilia). Furthermore, strategies to reduce antibiotic resistance are reviewed. Most important is institution of infection control policies including guidelines on surveillance, isolation of colonized patients and contact precautions, hand hygiene, decolonization measures and environmental decontamination. Antimicrobial stewardship, or striking the balance between an optimal antibiotic treatment for a patient and a minimal risk of development of antibiotic resistance, is another important strategy. Finally, optimizing of antibiotic dosage regimens and thus avoiding underdosage is essential to avoid selection of the most resistant subpopulation of bacteria during antibiotic treatment. Intensive care units with knowledge of local epidemiology of resistance, an effective infection control program and antimicrobial stewardship policy tailored to their specific needs, and using optimal antibiotic dosing regimens have both locally decreased the risk of an outbreak with multi-resistant bacteria, and maybe even more important help to reduce the development of antibiotic resistance.

Antibiotic prescription for critically ill patients is a complicated process because of the pharmacokinetic differences of this patient population with non-critically ill patients and the lack of robust informative studies. This article seeks to review the available literature describing dosing requirements for optimized treatment of critically ill patients and to discuss a framework to rationally address complex cases by outlining the suggested processes for optimal achievement of pharmacokinetic/ pharmacodynamic targets. A variety of papers exist describing the effect of pathophysiology on antibiotic kinetics. In the critically ill patient, dysfunction of almost any organ system can result in significant changes to drug volume of distribution and clearance. Dysfunction of the cardiovascular and renal systems in particular is problematic and can lead to potentially sub-therapeutic antibiotic concentrations in blood and in interstitial fluid. In response to altered pharmacokinetics, dose regimens that adhere to the pharmacodynamics of the antibiotic are essential. In the absence of validated dosing algorithms, therapeutic drug monitoring data and susceptibility data of the infecting pathogen should be inputted into a Bayesian software program that include population pharmacokinetic models to calculate dosing regimens that are personalized for the critically ill patient.

Recent advances in understanding tumor biology have provided new opportunities to develop effective approaches to treat patients with cancer. Intensive research on molecular pathways influencing genesis and progression of tumors has resulted in a panoply of potential drug targets. However, transforming growth factor beta (TGF-β) has kept a privileged position among cancer targets as it exerts a whole set of effects in malignant cancer progression. Particularly at later stages of tumor progression, many tumors produce excessive amounts of TGF-β. TGF-β supports angiogenesis and promotes cell motility and invasiveness as prerequisites of metastasis. Most importantly, TGF-β potently suppresses antitumor responses, e.g. through its effects on Tcells, B-cells, and antigen presenting cells, allowing tumors to escape from being recognized and eradicated by the immune system. The objective of this Special Issue of Current Pharmaceutical Biotechnology is to provide an overview on TGF-β biology and to reflect the current status of targeting TGF-β in oncology from the perspectives of scientists and clinicians, academics and pharmaceutical companies. At first A. Hinck & M. O'Connor McCourt give a comprehensive overview of recent progresses in characterizing structural features of the interaction of the three mammalian TGF-β isoforms TGF-β1, TGF-β2, TGF-β3 with the TGF-β receptor complex and work out both similarities and differences between the isoforms. H. Ikushima & K. Miyazono then describe the elements of intracellular TGF-β signaling and the multiple factors involved in its regulation. Considering the resulting complex network, it is not surprising that aberrant regulation of this pathway is involved in many diseases. L. van Meeteren, M.-J. Goumans & P. ten Dijke summarize the current understanding of TGF-β signaling in vascular development and angiogenesis, with a focus on recent insights into the role of the TGF-β type I receptor ALK1 and co-receptor endoglin in tumor angiogenesis. J. Buijs, P. Juarez & T. Guise outline the role of TGF-β in bone metastasis and discuss the limitations and opportunities of current treatment approaches. The following contributions review the specific role of TGF-β in various indications. E. Connolly & R. Akhurst work out the complexities of TGF-β action in regulation of two epithelial tumor types, namely squamous cell carcinoma and breast cancer. P. Hau, P. Jachimczak, J. Schlaier & U. Bogdahn highlight the critical role of TGF-β2 in high-grade glioma. The decisive role of this isoform in high-grade glioma patients was recognized early in TGF-β research. TGF-β2 has also an important role in two other indications reviewed in this edition. A. Hilbig & H. Oettle compile current knowledge on TGF-β in pancreatic cancer and A. Busse & U. Keilholz review the effects TGF-β in malignant melanoma with special emphasis on its vital role in immunosuppression. How can TGF-β be targeted? Overall, therapeutic interventions directed against TGF-β can either block excessive TGF-β production, neutralize its activity, or inhibit its receptor signaling. Several approaches are currently being developed. S. Lonning, J. Mannick & J. McPherson put together results of experimental animal and human clinical studies on antibody-mediated neutralization of TGF-β. L. Ling & W.-C. Lee then give an overview on the development of small molecules for the inhibition of TGF-β type I receptor kinase (ALK5) as a means to interrupt TGF-β-signaling. Finally, F. Jaschinski, T. Rothhammer, P. Jachimczak, C. Seitz, A. Schneider & K.-H. Schlingensiepen present the antisense oligodeoxynucleotide trabedersen for the targeted treatment of patients with tumors overproducing TGF-β2. I sincerely hope that this Special Issue provides insightful reading and contributes to raise awareness for TGF-β as a highly attractive therapeutic target in oncology.

TGF-β isoforms (TGF-β1, -β2, and -β3) are secreted signaling ligands that stimulate the expression of protein components of the extracellular matrix, regulate the growth and differentiation of epithelial cells, modulate immune cell function, and play roles in the development of several essential organs, including the heart and lungs. The importance of the TGF-βs is underscored by their conservation among vertebrates and by their demonstrated roles in a variety of human diseases, including tissue fibrosis and cancer. The objective of this review is to highlight recent progress in characterizing the structures of the three TGF-β isoforms in complex with their receptors, and to compare these with one another as well as with other members of the superfamily. Although the structural information and accompanying biophysical studies emphasize the shared ancestry of TGF-βs, they also provide insight as to how the TGF-βs diverged from other members of the superfamily and one another to fulfill distinct roles in vivo. The similarities and differences by which the isoforms bind their receptors present unique opportunities for designing pan-isoform and isoform-specific ligand traps and progress toward developing these is described.

Transforming growth factor (TGF)-β signaling has been implicated as an important regulator of almost all major cell behaviors, including proliferation, differentiation, cell death, and motility. Which cell responses are induced or suppressed in response to TGF-β depends on the cell type and the context in which TGF-β signaling is received. TGF-β ligands, their receptors, and intracellular Smad effectors lie in the center of TGF-β signaling. TGF-β ligands signal via receptor serine/threonine kinases that phosphorylate and activate Smad proteins as well as other signaling molecules. Smad complexes associate with chromatin and regulate transcription, defining the biological response of a cell to TGF-β stimulation. In addition, numerous factors constitute complex networks to regulate TGF-β signaling and to provide this cytokine with the ability to induce cellular context-specific cell responses. Perturbation of the network is strongly involved in various pathological situations, including cancer and fibrosis. In this review, we consider the basic machinery of TGF-β signaling and describe several factors which make up TGF-β signaling networks. We also address major TGF-β-induced cell responses involved in several physiological and pathological conditions, including cell proliferation, fibrosis, and epithelial-mesenchymal transition.

Angiogenesis, the formation of new blood vessels is essential for diverse physiological processes such as development, but also for pathological conditions like tumor growth. Most studied in this context are tyrosine kinase signaling pathways such as those involving vascular endothelial growth factor (VEGF). There is however accumulating evidence that more pathways are as essential for angiogenesis. Knockout studies of factors in transforming growth factor β (TGF-β) signaling have for example showed that also this pathway is indispensable for angiogenesis. This review highlights our understanding of TGF-β signaling in vascular development and angiogenesis. In particular, we focus on recent insights into the role of the TGF-β type I receptor ALK1 and co-receptor endoglin in tumor angiogenesis, which provide opportunities for the development of new anti-angiogenesis therapies for treatment of cancer patients.

Bone is one of the most common organs to be affected in patients with metastatic cancer. These bone metastases are often accompanied by bone destruction, bone fractures, pain, and hypercalcemia. Transforming growth factor-β (TGF-β) is a major bone-derived factor that is released in active form upon osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic cells to secrete factors that further drive osteolytic destruction of the bone adjacent to the tumor, categorizing TGF-β as a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between tumor cells and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. In this review, preclinical and clinical data are evaluated for the potential use of TGF-β inhibitors in clinical practice to treat bone metastases.

Many advanced tumors produce excess amounts of Transforming Growth Factor-β (TGF-β), which is a potent growth inhibitor of normal epithelial cells. However, in tumors its homeostatic action on cells can be diverted along several alternative pathways. Thus, TGF-β signaling has been reported to elicit a preventative or tumor suppressive effect during the earlier stages of tumorigenesis, but later in tumor development, when carcinoma cells become refractory to TGF-β-mediated growth inhibition, response to TGF-β signaling elicits predominantly tumor progressing effects. This is not a simple switch from suppression to progression, but more like a rheostat, involving multiple complementary and antagonizing activities that slowly tip the balance from one to the other. This review will focus on the multiple activities of TGF-β in regulation of two epithelial tumor types, namely squamous cell carcinoma and breast cancer. Basic findings in current mouse models of cancer are presented, as well as a discussion of the complicating issue of outcome of altered TGFβ signaling depending on genetic variability between mouse strains. This review also discusses the role TGF-β within the tumor microenvironment particularly its ability to polarize the microenvironment towards a pro-tumorigenic milieu.

High-grade gliomas are the most common primary tumors in the central nervous system (CNS) in adults. Despite efforts to improve treatment by combination therapies (neurosurgery, radio- and chemotherapy), high-grade glioma patients still have a grim prognosis, indicating an urgent need for new therapeutic approaches. The molecular processes of gliomagenesis are being unraveled, and novel targeted therapeutic strategies to defy high-grade gliomas are emerging. Transforming growth factor-beta (TGF-β), in particular the TGF-β2 isoform, has been identified as a key factor in the progression of malignant gliomas. TGF-β2, originally described as “glioblastoma-derived T-cell suppressor factor”, is associated with the immuno-suppressed status of patients with glioblastoma, and is therefore responsible for loss of tumor immune surveillance. Elevated TGF-β2 levels in tumors and in the plasma of patients have been associated with advanced disease stage and poor prognosis. Consequently, a targeted strategy to modulate TGF-β2 signaling is highly promising. The antisense oligonucleotide trabedersen (AP 12009) that specifically blocks TGF-β2 mRNA will be the main focus of this review. In three phase I/II studies and a randomized, active-controlled dose-finding phase IIb study, trabedersen treatment of high-grade glioma patients with recurrent or refractory tumor disease led to long-lasting tumor responses and so far promising survival data. On the basis of these data the currently ongoing phase III study SAPHIRRE was initiated.

Pancreatic cancer has high incidence and mortality rates, and effective treatment remains a clinical challenge. As deregulation of the cytokine transforming growth factor beta (TGF-β) contributes to the progression of pancreatic carcinoma, the TGF-β pathway has been targeted using various strategies, including small molecule inhibitors of TGF-βRI, TGF-β-specific neutralizing antibodies and antisense compounds. As increased TGF-β2 levels in serum or tumor tissue of patients with pancreatic cancer correlated with poor prognosis, inhibition of TGF-β2 synthesis via the antisense oligonucleotide trabedersen (AP 12009) is a promising approach.