Pharmacodynamic Considerations Research Articles

Responsible, Safe, and Effective Use of Antithrombotics and Anticoagulants in Patients Undergoing Interventional Techniques: American Society of Interventional Pain Physicians (ASIPP) Guidelines

Interventional pain management involves diagnosis and treatment of chronic pain. This specialty utilizes minimally invasive procedures to target therapeutics to the central nervous system and the spinal column. A subset of patients encountered in interventional pain are medicated using anticoagulant or antithrombotic drugs to mitigate thrombosis risk. Since these drugs target the clotting system, bleeding risk is a consideration accompanying interventional procedures. Importantly, discontinuation of anticoagulant or antithrombotic drugs exposes underlying thrombosis risk, which can lead to significant morbidity and mortality especially in those with coronary artery or cerebrovascular disease. This review summarizes the literature and provides guidelines based on best evidence for patients receiving anti-clotting therapy during interventional pain procedures. Best evidence synthesis. To provide a current and concise appraisal of the literature regarding an assessment of the bleeding risk during interventional techniques for patients taking anticoagulant and/or antithrombotic medications. A review of the available literature published on bleeding risk during interventional pain procedures, practice patterns and perioperative management of anticoagulant and antithrombotic therapy was conducted. Data sources included relevant literature identified through searches of EMBASE and PubMed from 1966 through August 2018 and manual searches of the bibliographies of known primary and review articles. 1. There is good evidence for risk stratification by categorizing multiple interventional techniques into low-risk, moderate-risk, and high-risk. Also, their risk should be upgraded based on other risk factors.2. There is good evidence for the risk of thromboembolic events in patients who interrupt antithrombotic therapy. 3. There is good evidence supporting discontinuation of low dose aspirin for high risk and moderate risk procedures for at least 3 days, and there is moderate evidence that these may be continued for low risk or some intermediate risk procedures.4. There is good evidence that discontinuation of anticoagulant therapy with warfarin, heparin, dabigatran (Pradaxa®), argatroban (Acova®), bivalirudin (Angiomax®), lepirudin (Refludan®), desirudin (Iprivask®), hirudin, apixaban (Eliquis®), rivaroxaban (Xarelto®), edoxaban (Savaysa®, Lixiana®), Betrixaban(Bevyxxa®), fondaparinux (Arixtra®) prior to interventional techniques with individual consideration of pharmacokinetics and pharmacodynamics of the drugs and individual risk factors increases safety.5. There is good evidence that diagnosis of epidural hematoma is based on severe pain at the site of the injection, rapid neurological deterioration, and MRI with surgical decompression with progressive neurological dysfunction to avoid neurological sequelae.6. There is good evidence that if thromboembolic risk is high, low molecular weight heparin bridge therapy can be instituted during cessation of the anticoagulant, and the low molecular weight heparin can be discontinued 24 hours before the pain procedure.7. There is fair evidence that the risk of thromboembolic events is higher than that of epidural hematoma formation with the interruption of antiplatelet therapy preceding interventional techniques, though both risks are significant.8. There is fair evidence that multiple variables including anatomic pathology with spinal stenosis and ankylosing spondylitis; high risk procedures and moderate risk procedures combined with anatomic risk factors; bleeding observed during the procedure, and multiple attempts during the procedures increase the risk for bleeding complications and epidural hematoma.9. There is fair evidence that discontinuation of phosphodiesterase inhibitors is optional (dipyridamole [Persantine], cilostazol [Pletal]. However, there is also fair evidence to discontinue Aggrenox [dipyridamole plus aspirin]) 3 days prior to undergoing interventional techniques of moderate and high risk. 10. There is fair evidence to make shared decision making between the patient and the treating physicians with the treating physician and to consider all the appropriate risks associated with continuation or discontinuation of antithrombotic or anticoagulant therapy.11. There is fair evidence that if thromboembolic risk is high antithrombotic therapy may be resumed 12 hours after the interventional procedure is performed.12. There is limited evidence that discontinuation of antiplatelet therapy (clopidogrel [Plavix®], ticlopidine [Ticlid®], Ticagrelor [Brilinta®] and prasugrel [Effient®]) avoids complications of significant bleeding and epidural hematomas.13. There is very limited evidence supporting the continuation or discontinuation of most NSAIDs, excluding aspirin, for 1 to 2 days and some 4 to 10 days, since these are utilized for pain management without cardiac or cerebral protective effect. The continued paucity of the literature with discordant recommendations. Based on the survey of current literature, and published clinical guidelines, recommendations for patients presenting with ongoing antithrombotic therapy prior to interventional techniques are variable, and are based on comprehensive analysis of each patient and the risk-benefit analysis of intervention. Perioperative bleeding, bleeding risk, practice patterns, anticoagulant therapy, antithrombotic therapy, interventional techniques, safety precautions, pain.

Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein.

According to the free drug hypothesis only the unbound drug is available to act at physiological sites of action, and as such the importance of plasma protein binding primarily resides in its impact on pharmacokinetics and pharmacodynamics. Of the major plasma proteins, alpha-1-acid glycoprotein (AAG) represents an intriguing one primarily due to the high affinity, low capacity properties of this protein. In addition, there are marked species and age differences in protein expression, homology and drug binding affinity. As such, a thorough understanding of drug binding to AAG can help aid and improve the translation of pharmacokinetic/pharmacodynamic (PK/PD) relationships from preclinical species to human as well as adults to neonates. This review provides a comprehensive overview of our current understanding of the biochemistry of AAG; endogenous function, impact of disease, utility as a biomarker, and impact on PK/PD. Experimental considerations are discussed as well as recommendations for understanding the potential impact of AAG on PK through drug discovery and early development.

Pharmacokinetic and Pharmacodynamic Considerations in the Design of Therapeutic Antibodies.

The design and development of therapeutic monoclonal antibodies (mAbs) through optimizing their pharmacokinetic (PK) and pharmacodynamic (PD) properties is crucial to improve efficacy while minimizing adverse events. Many of these properties are interdependent, which highlights the inherent challenges in therapeutic antibody design, where improving one antibody property can sometimes lead to changes in others. Here, we discuss optimization approaches for PK/PD properties of therapeutic mAbs.

Pharmacokinetic and pharmacodynamic considerations for the clinical efficacy of perampanel in focal onset seizures

ABSTRACTIntroduction: Medical therapy is the mainstay of management of epilepsy. Despite the increasing number of available antiepileptic drugs (AEDs), approximately one-third of epileptic patients do not have adequate control of seizures. There is still a need for the development of new AEDs with enhanced effectiveness and tolerability.Areas covered: The present manuscript is based on an Internet and PubMed search (January 2005 to August 2018). It is focused on pharmacokinetic and clinical data of perampanel (PER) for the treatment of epilepsy.Expert opinion: PER has a novel mechanism of action, which opens up new options for a rational combination therapy. Phase III trials have demonstrated the efficacy and safety of PER as adjunctive therapy for the treatment of partial-onset seizures (POS) and primary generalized tonic–clonic seizures in patients aged ≥12 years. PER is also approved by FDA as monotherapy for the treatment of POS. A clinical trial is ongoing to verify the efficacy and safety of PER monotherapy in untreated patients with POS. In the future, head-to-head comparisons are needed to determine the exact position of PER relative to other AEDs. Moreover, further studies are needed to evaluate the efficacy and safety of PER in patients aged <12 years.Abbreviations: 4βOHC: 4β-hydroxycholesterol; AUC: area under the curve; CBZ: Carbamazepine; CLCr: creatinine clearance; Cmax: maximum plasma concentration; CYP: cytochrome P; EIAED: enzyme-inducing antiepileptic drug; EMA: European Medicines Agency; FDA: Food and Drug Administration; GI: gastrointestinal; OXC: oxcarbazepine; PER: perampanel; PGTC: primary generalized tonic-clonic; PHT: phenytoin; POS: partial-onset seizures; QD: once-daily; TEAE: treatment-emergent adverse event; Tmax: median time to reach peak concentration; UGT: uridine diphosphoglucose-glucuronosyltransferase; VPA: valproic acid

Suboptimal Clinical Response Rates with Newer Antibiotics Among Patients with Moderate Renal Impairment: Review of the Literature and Potential Pharmacokinetic and Pharmacodynamic Considerations for Observed Findings

A number of antibacterial agents have emerged into the U.S. market in the last 2 decades to address growing concerns of antimicrobial resistance. These agents have demonstrated noninferiority to comparators for treatment of a range of complicated infections in their respective clinical trials. However, with select agents, a trend of reduced therapeutic efficacy was observed among study patients with baseline renal impairment. This phenomenon was seen in phase III studies involving ceftazidime-avibactam, ceftolozane-tazobactam, daptomycin, and telavancin. Although these were largely post hoc findings among small subpopulations, this observation is still concerning, given that renal impairment is a common occurrence among patients in real-world care settings. Cautions for use in this population are featured in the prescribing information of all four agents. Although well-defined reasons for these findings across trials are diverse or unknown, several potential pharmacokinetic and pharmacodynamic explanations for these discordant response rates exist. In this review, we summarize the phase III studies that observed lower response rates with ceftazidime-avibactam, ceftolozane-tazobactam, daptomycin, and telavancin relative to their comparators among patients with moderate renal impairment, discuss potential explanations for the observed findings, provide considerations for future antibiotic development, and offer strategies for optimizing antibiotic dosage selection among patients with moderate renal impairment in clinical settings. Although all of these agents are discussed, ceftazidime-avibactam is used as a motivating example to demonstrate the implications of inappropriate dosage selection.

Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen.

IntroductionAntibiotics have greatly reduced the morbidity and mortality due to infectious diseases. Although antibiotic resistance is not a new problem, its breadth now constitutes a significant threat to human health. One strategy to help combat resistance is to find novel ways to use existing drugs, even those that display high rates of resistance. For the pathogens Escherichia coli and Pseudomonas aeruginosa, pairs of antibiotics have been identified for which evolution of resistance to drug A increases sensitivity to drug B and vice versa. These research groups have proposed cycling such pairs to treat infections, and similar treatment strategies are being investigated for various cancer forms as well. While an exciting treatment prospect, no cycling experiments have yet been performed with consideration of pharmacokinetics and pharmacodynamics. To test the plausibility of such schemes and optimize them, we create a mathematical model with explicit pharmacokinetic/pharmacodynamic considerations.Materials and methodsWe evaluate antibiotic cycling protocols using pairs of such antibiotics and investigate the speed of ascent of multiply resistant mutants.ResultsOur analyses show that when using low concentrations of antibiotics, treatment failure will always occur due to the rapid ascent and fixation of resistant mutants. However, moderate to high concentrations of some combinations of bacteriostatic and bactericidal antibiotics with multiday cycling prevent resistance from developing and increase the likelihood of treatment success.ConclusionOur results call for guarded optimism in application and development of such treatment protocols.

Treatment Options for Carbapenem- Resistant Gram-Negative Infections.

Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is increasingly true in Germany as well. The organisms in question include enterobacteriaceae such as Klebsiella pneumoniae and Escherichia coli and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As the carbapenems have been the gold standard to date for the systemic treatment of serious infections with Gram-negative bacteria, carbapenem resistance presents new and difficult challenges in therapeutic decision-making, particularly because of the high frequency of coresistance. This review is based on pertinent publications retrieved by a selective search in PubMed and on other applicable literature. Multiresistant Gram-negative (MRGN) pathogens are classified in Germany according to their resistance to four different classes of antibiotics; fluoroquinolones, piperacillin, third-generation cephalosporins, and carbapenems. Quadruple MRGN pathogens are resistant to all four groups, triple MRGN pathogens to three of them. There are a number of therapeutic alternatives to carbapenems that can be applied with the aid of sensitive microbiological and/or molecular genetic testing. The following antibiotics are often the only ones that can be used to treat quadruple MRGN pathogens: colistin, aminoglycosides, tigecycline, fosfomycin, ceftazidime/avibactam, and ceftolozan/tazobactam. Carbapenems, too, may still be an option in certain situations. There is also evidence that combinations of antibiotics against which the pathogen is resistant individually can some- times be a valid treatment option; these include combinations of colistin with one or two carbapenems. The treatment of severe infection with carbapenem-resistant pathogens should be individualized and carried out in an interdisciplinary framework, in consideration of antibiotic pharmacokinetics and pharmacodynamics in each case. The treat- ment options are based on evidence from in vitro studies, retrospective studies, and case series, which must be interpreted with caution. Randomized clinical trials are needed to test each of the various combined approaches.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of unknown etiology, probably caused by a combination of genetic and environmental factors. The treatment of patients with active UC depends on the severity, localization and history of IBD medication. According to the classic step-up approach, treatment with 5-aminosalicylic acid compounds is the first step in the treatment of mild to moderately active UC. Corticosteroids, such as prednisolone are used in UC patients with moderate to severe disease activity, but only for remission induction therapy because of side effects associated with long-term use. Thiopurines are the next step in the treatment of active UC but monotherapy during induction therapy in UC patients is not preferred because of their slow onset. Therapeutic drug monitoring (TDM) of the pharmacologically active metabolites of thiopurines, 6-thioguanine nucleotide (6-TGN), has proven to be beneficial. Thiopurine S-methyltransferase (TMPT) plays a role in the metabolic conversion pathway of thiopurines and exhibits genetic polymorphism; however, the clinical benefit and relevance of TPMT genotyping is not well established. In patients with severely active UC refractory to corticosteroids, calcineurin inhibitors such as ciclosporin A (CsA) and tacrolimus are potential therapeutic options. These agents usually have a rather rapid onset of action. Monoclonal antibodies (anti-tumor necrosis factor [TNF] agents, vedolizumab) are the last pharmacotherapeutic option for UC patients before surgery becomes inevitable. Body weight, albumin status and antidrug antibodies contribute to the variability in the pharmacokinetics of anti-TNF agents. Additionally, the use of concomitant immunomodulators (thiopurines/methotrexate) lowers the rate of immunogenicity, and therefore the concomitant use of anti-TNF therapy with an immunomodulator may confer some advantage compared with monotherapy in certain patients. TDM of anti-TNF agents could be beneficial in patients with primary nonresponse and secondary loss of response. The potential benefit of applying TDM during vedolizumab treatment has yet to be determined.

Pharmacokinetic and Pharmacodynamic Considerations of Antibiotics of Last Resort in Treating Gram-Negative Infections in Adult Critically Ill Patients.

We provide an overview of antimicrobials that are considered last resort for the treatment of resistant gram-negative infections in adult critically ill patients. The role in therapy, pharmacodynamic (PD) goals, and pharmacokinetic (PK) changes in critical illness for aminoglycosides, polymyxins, tigecycline, fosfomycin, and fluoroquinolones are summarized. Altered PK in septic patients in the intensive care unit (ICU) is observed with many of our agents of last resort. Based on the available literature, dosage adjustments may be required to optimize PK parameters and meet PD targets for most effective bacterial killing. Data is limited, studies are conducted in heterogeneous patient populations, and conclusions are frequently conflicting. Strategic dosing regimens such as high-dose extended interval dosing of aminoglycosides or loading doses with colistin and polymyxin B are examples of ways to optimize antibiotic PK in critically ill patients. Benefits of these strategies must be balanced with risks of increased toxicity. Patients with resistant gram-negative infections may present with septic shock in the ICU. Sepsis can significantly alter the PK of antibiotics and require dosage adjustments to attain optimal drug levels. An understanding of PK and PD properties of these agents of last resort will help to maximize therapeutic efficacy while minimizing toxic effects.

Dose adjustment of anti-infective drugs in patients with renal failure and renal replacement therapy in intensive care medicine : Recommendations from the renal section of the DGIIN, ÖGIAIN and DIVI

Many anti-infective drugs require dose adjustments in critically ill patients with acute kidney injury (AKI) and renal replacement therapy, in order to achieve adequate therapeutic drug concentrations. The fundamental pharmacokinetic and pharmacodynamic principles of drug dose adjustment are presented. Recommendations on anti-infective drug dosage in intensive care are provided. We established dose recommendations of selected anti-infective drugs based on information in the summary of product characteristics, published studies and recommendations, pharmacokinetic and pharmacodynamic considerations, and the experience and expert opinion of the authors. Out of atotal of 37anti-infective drugs (31antibiotics, 2antivirals, 4antifungals) 8can be administered independent of renal function. For 29anti-infective drugs, aspecific recommendation on drug dosage could be made in case of intermittent hemodialysis and for 24anti-infective drugs in case of continuous hemo(dia)filtration. Recommendations on dosing of important anti-infective drugs in critically ill patients with AKI and renal replacement therapy are provided.

Intravenous Push Administration of Antibiotics: Literature and Considerations.

Intravenous (IV) push administration can provide clinical and practical advantages over longer IV infusions in multiple clinical scenarios, including in the emergency department, in fluid-restricted patients, and when supplies of diluents are limited. In these settings, conversion to IV push administration may provide a solution. This review compiles available data on IV push administration of antibiotics in adults, including preparation, stability, and administration instructions. Prescribing information, multiple tertiary drug resources, and primary literature were consulted to compile relevant data. Several antibiotics are Food and Drug Administration-approved for IV push administration, including many beta-lactams. In addition, cefepime, ceftriaxone, ertapenem, gentamicin, and tobramycin have primary literature data to support IV push administration. While amikacin, ciprofloxacin, imipenem/cilastatin, and metronidazole have limited primary literature data on IV push administration, available data do not support that route. In addition, a discussion on practical considerations, such as IV push best practices and pharmacodynamic considerations, is provided.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Inflammatory Bowel Disease

According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.

Pharmacokinetic and Pharmacodynamic Considerations for the Use of Monoclonal Antibodies in the Treatment of Bacterial Infections

Antibiotic-resistant bacterial pathogens are increasingly implicated in hospital- and community-acquired infections. Recent advances in monoclonal antibody (mAb) production and engineering have led to renewed interest in the development of antibody-based therapies for treatment of drug-resistant bacterial infections. Currently, there are three antibacterial mAb products approved by the Food and Drug Administration (FDA) and at least nine mAbs are in clinical trials. Antibacterial mAbs are typically developed to kill bacteria or to attenuate bacterial pathological activity through neutralization of bacterial toxins and virulence factors. Antibodies exhibit distinct pharmacological mechanisms from traditional antimicrobials and, hence, cross-resistance between small molecule antimicrobials and antibacterial mAbs is unlikely. Additionally, the long biological half-lives typically found for mAbs may allow convenient dosing and vaccine-like prophylaxis from infection. However, the high affinity of mAbs and the involvement of the host immune system in their pharmacological actions may lead to complex and nonlinear pharmacokinetics and pharmacodynamics. In this review, we summarize the pharmacokinetics and pharmacodynamics of the FDA-approved antibacterial mAbs and those are currently in clinical trials. Challenges in the development of antibacterial mAbs are also discussed.

Venous thromboembolism prophylaxis in medically ill patients: a mixed treatment comparison meta-analysis.

The American College of Chest Physicians guidelines recommend unfractionated heparin (UFH), low molecular weight heparins (LMWHs) or fondaparinux for prevention of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in medically-ill patients. Direct oral anticoagulants (DOACs) have been evaluated relative to enoxaparin for VTE prophylaxis though head-to-head comparisons of these agents are lacking. Therefore, we conducted a mixed treatment comparisons meta-analysis to evaluate the safety and efficacy of established treatments and DOACs for VTE prophylaxis in medically-ill patients. A comprehensive literature search was conducted to identify randomized trials evaluating UFH, LMWHs or DOACS for the prevention of VTE in medically ill patients. Articles were retrieved and cross-referenced for additional trials, evaluated and entered into ADDIS (version 1.16.6) to generate direct and indirect treatment comparisons for VTE, DVT, PE, death from any cause, and bleeding. Ten articles were included and eight anticoagulants were evaluated in a treatment network representing data on 28,382 patients. We found each treatment had similar efficacy in preventing VTE, DVT, PE, death from any cause and each had similar risk of minor and major bleeding. Overall, placebo was associated with more VTE and DVT events compared to LMWHs and DOACs. We found that UFH, LMWHs and DOACs are comparable in preventing VTE, DVT, PE, and death from any cause and in association with minor and major bleeding. Anticoagulant selection for VTE prophylaxis in medically-ill patients should be individualized by patient characteristics, risks and preferences along with specific pharmacokinetic and pharmacodynamic considerations.

ЭФФЕКТИВНОСТЬ ИСПОЛЬЗОВАНИЯ НОВОГО ИММОБИЛИЗОВАННОГО ПРОБИОТИКА В КОМПЛЕКСЕ ЛЕЧЕНИЯ БОЛЬНЫХ ТУБЕРКУЛЕЗОМ ЛЕГКИХ

The study was conducted in order to evaluate the efficiency of adding immobilized probiotic biologically active food supplement of LB-Complex L to integral treatment of pulmonary tuberculosis. Changes of colon microorganism community in pulmonary tuberculosis patients including those with multiple drug resistance were studied in two groups of patients: receiving only basic treatment and basic treatment with the immobolized probiotic of LB-Complex L as a food supplement. The algorithm of probiotic intake has been offered with the consideration of pharmacodynamics of anti-tuberculosis drugs. The offered algorithm proved to be effective for prevention of disorders in microorganism community, enhancement of adherence to treatment, reduction of frequency, severity and duration of side effects to anti-tuberculosis drugs.

Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax.

Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents. Unique treatment-related adverse events including bleeding and atrial fibrillation with ibrutinib, hepatotoxicity with idelalisib, and tumor lysis syndrome with venetoclax can be severe and dose limiting. Furthermore, dose adjustments for organ dysfunction may also be warranted. Here, we review the available literature on the pharmacokinetic and pharmacodynamic properties of these novel agents to guide the reader in the appropriate use of ibrutinib, idelalisib, and venetoclax.

Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations.

Therapeutic drug monitoring (TDM) may be required to achieve optimal clinical outcomes in the setting of significant pharmacokinetic variability, a situation that applies to a number of anti-mould therapies. The majority of patients receiving itraconazole should routinely be managed with TDM. Voriconazole exhibits highly variable inter-individual pharmacokinetics, and a trough concentration of 1.0-5.5 mg/L is widely accepted although it is derived from relatively low-quality evidence. The case for TDM of posaconazole is currently in a state of flux following the introduction of a newer tablet formulation with improved oral bioavailability, but it may be indicated when used for either prophylaxis or treatment of established disease. The novel broad-spectrum azole drug isavuconazole does not currently appear to require TDM but 'real-world' data are awaited and TDM could be considered in selected clinical cases. For both polyene and echinocandin agents, there are insufficient data regarding the relationship between serum concentrations and therapeutic outcomes to support the routine use of TDM. A number of practical challenges to the implementation of TDM in the treatment of invasive mould infections remain unsolved. The delivery of TDM as a future standard of care will require real-time measurement of drug concentrations at the bedside and algorithms for dosage adjustment. Finally, measures of pharmacodynamic effect are required to deliver therapy that is truly individualized.

Pharmacologic Consideration in the Elderly Trauma Patient

Purpose of review Elderly trauma patients (≥65 years) account for 12% of trauma admissions, and trauma represents the fifth leading cause of death in this population. Critically ill elderly patients are among the most complex population to optimize medications. This review will discuss pharmacokinetic and pharmacodynamic considerations in older ICU patients based on physiologic changes related to aging.

Pharmacological sedation management in the paediatric intensive care unit.

This review addresses sedation management on paediatric intensive care units and possible gaps in the knowledge of optimal sedation strategies. We present an overview of the commonly used sedatives and their pharmacokinetic and pharmacodynamic considerations in children, as well as the ongoing studies in this field. Also, sedation guidelines and current sedation strategies and assessment methods are addressed. This review shows that evidence and pharmacokinetic data are scarce, but fortunately, there is an active research scene with promising new PK and PD data of sedatives in children using new study designs with application of advanced laboratory methods and modelling. The lack of evidence is increasingly being recognized by authorities and legislative offices such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). The population in question is very heterogeneous and this overview can aid clinicians and researchers in moving from practice-based sedation management towards more evidence- or model-based practice. Still, paediatric sedation management can be improved in other ways than pharmacology only, so future research should aim on sedation assessment and implementation strategies of protocolized sedation as well.

Incorporating pharmacodynamic considerations into caffeine therapeutic drug monitoring in preterm neonates.

BackgroundThis study sought to assess the pharmacokinetic and pharmacodynamic relationships of caffeine citrate therapy in preterm neonates who had therapeutic drug monitoring (TDM) in the post-extubation period.MethodsA retrospective observational study was conducted in preterm neonates who received caffeine citrate therapy for apnea of prematurity and had TDM done in the post-extubation period between January 2006 and October 2011. The relationships between pharmacodynamic effects (heart rate, respiratory rate, episodes of apnea, adverse events) and caffeine serum concentrations were explored.ResultsA total of 177 blood samples were obtained from 115 preterm neonates with a median (range) gestational age of 29 (24 – 33) weeks and birth weight of 1230 (607 – 2304) kg. Caffeine citrate therapy was initiated at a median (interquartile range) postnatal age of 1 (1 – 3) day and TDM was performed at a postnatal age of 15 (10 – 24) days. No direct correlations were found between respiratory rate or apneic episodes and caffeine serum concentrations; however, heart rate and caffeine serum concentrations were significantly correlated (p < 0.05). Dosing regimen of 40/5 mg/kg q12h (loading dose/maintenance dose, time interval) led to similar endotracheal re-intubation rate but increased percentage of patients experiencing tachycardia compared to the standard regimen of 20/5 mg/kg q24h (44.7 % vs 10.2 %, p < 0.001).ConclusionBased on this retrospective study, no correlation between episodes of apnea and caffeine serum concentrations was found in neonates who had TDM of caffeine citrate therapy in the post-extubation period, whereas a significant association between tachycardia and concentrations existed. Notwithstanding the absence of severe adverse reactions, TDM should be considered in critically ill neonates with unexplained adverse effects, such as tachycardia.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-016-0065-x) contains supplementary material, which is available to authorized users.