Current Clinical Pharmacology - Volume 8, Issue 1, 2013
Volume 8, Issue 1, 2013
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Plasma Pharmacokinetics of Antimicrobial Agents in Critically Ill Patients
By Federico PeaPrompt optimal antimicrobial treatment in critically ill patients is mandatory and must be achieved not only in terms of spectrum of activity, but also in terms of exposure at the infection site. Plasma profile of antimicrobial agents may represent a valid surrogate marker of drug exposure and allow to identify the correct dosage for a given drug. However, in the critically ill patients the pharmacokinetic behavior of antimicrobials may be altered by some very peculiar pathophysiological conditions, so that dosages significantly different from those used in clinically stable patients or from those originally studied in healthy volunteers for regulatory purposes may often be needed in order to ensure optimal plasma drug exposure in such population. This is especially true for hydrophilic antimicrobials (aminoglycosides, betalactams, glycopeptides, lipopeptides, echinocandins, fluconazole, acyclovir, ganciclovir) whose volume of distribution and clearance may be significantly altered by these conditions. These aspects are particularly relevant in patients with severe sepsis or with septic shock for whom the time for being considered as a special population to be studied apart from the general population has probably come. From the healthcare system perspective, this means that individualization of antimicrobial therapy by means of a real time therapeutic drug monitoring coupled with clinical pharmacological advice should be considered an invaluable tool for optimizing antimicrobial therapy and for the containment of microbial resistance in this setting.
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Continuous Infusion of Antibiotics in Critically Ill Patients
Authors: Piotr Smuszkiewicz, Edyta SzaÅ,ek, Hanna Tomczak and Edmund GrzeskowiakAntibiotics are the most commonly used drugs in intensive care unit patients and their supply should be based on pharmacokinetic/pharmacodynamic rules. The changes that occur in septic patients who are critically ill may be responsible for subtherapeutic antibiotic concentrations leading to poorer clinical outcomes. Evolving in time the disturbed pathophysiology in severe sepsis (high cardiac output, glomerular hyperfiltration) and therapeutic interventions (e.g. haemodynamically active drugs, mechanical ventilation, renal replacement therapy) alters antibiotic pharmacokinetics mainly through an increase in the volume of distribution and altered drug clearance. The lack of new and efficacious drugs and increased bacterial resistance are current problems of contemporary antibiotic therapy. Although intermittent administration is a standard clinical practice, alternative methods of antibiotic administration are sought, which may potentialise effects and reduce toxicity as well as contribute to inhibition of bacterial resistance. A wide range of studies prove that the application of continuous infusion of time-dependent antibiotics (beta-lactams, glycopeptides) is more rational than standard intermittent administration. However, there are also studies which do not confirm the advantage of one method over the other. In spite of controversy the continuous administration of this group of antibiotics is common practice, because the results of both studies point to the higher efficacy of this method in critically ill patients. Authors reviewed the literature to determine whether any clinical benefits exist for administration of time-dependent antibiotics by continuous infusion. Definite specification of the clinical advantage of administration this way over standard dosage requires a large-scale multi-centre randomised controlled trial.
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Antimicrobial Drug Interactions in the Critically Ill Patients
Authors: Jose M. Pereira and Jose A. PaivaCritically ill patients are typically polymedicated and therefore at a high risk for potential drug interactions. Clinical consequences of drugs interactions vary in severity from mild to lethal events. Since infection is an important issue in the Intensive Care Unit (ICU), a significant number of patients will receive an antimicrobial at some stage during their ICU admission. Therefore an adequate knowledge about possible interactions between antimicrobials and other drugs is necessary, since it may not only impact on the effectiveness of the antimicrobial but also in the incidence of drug adverse events. This review describes important drug interactions involving antimicrobials in the critically ill patient.
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Effects of Renal Replacement Therapy on Antimicrobial Therapy
Authors: Matthias G. Vossen and Florian ThalhammerAntimicrobial therapy in patients receiving renal replacement therapy (RRT) is challenging due to the varying pharmacokinetic profile of each drug - membrane - technique combination. Renally excreted drugs are usually affected by RRT to a much higher extend than hepatically excreted drugs. However, highly protein bound drugs might be eliminated during RRTs regardless of their usual route of elimination through the formation of a protein membrane within the filter. Beta-lactames pose a good example: most beta-lactames are excreted renally as unchanged drug. However, some betalactames, e.g. flucloxacillin or ceftriaxone adhere to the filter membrane due to their strong protein-drug interaction. Depending on the implemented RRT different administration regimens should be chosen. While beta-lactames may be administered three times daily as well as continuously during continuous RRT, they should be given only once after each hemodialysis session. Aminoglycosides on the other hand should best be given previous to HD to allow for high peak and low through concentrations due to their small therapeutic index and high toxicity. The current Recommendation for glycopeptides in hemodialysis is a post-HD administration. In both groups, aminoglycosides as well as glycopeptides drug monitoring is mandatory. For chinolones the standard dosing intervals should remain unchanged, however they require a significant reduction of the dose, with the exception of moxifloxacin which is excreted hepatically. Until now there are few publications guiding the clinician to the correct dosing schemes in RRT. This review aims to give dosage recommendations for a broad collection of currently used antimicrobial agents and should be applicable for all types of presently employed membranes.
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Methods to Measure Target Site Penetration of Antibiotics in Critically Ill Patients
Authors: Richard Schwameis and Markus ZeitlingerWhile several tools are necessary to repair a car, the engineer knows exactly which instrument he has to utilize at different parts of the broken machine. Likewise, depending on the information we are interested in, we have to choose different tools to investigate and consecutively understand the multiple aspects that are involved in pharmacokinetics of antimicrobial agents in critically ill patients. Some techniques, like blood sampling, microdialysis or positrons emission tomography (PET) will allow for obtaining continues concentration time profiles while others like bronchoalveolar lavage (BAL), biopsy or surgical tissue samples can only be used a limited number of times per subject. PET and methods based on tissue homogenization will deliver an average of the actual concentrations in intra – and extracellular compartments while investigations in isolated blood cells or microdialysis allow for more distinguished allocation of a concentration to a defined compartment. The present review aims at discussing the advantages and disadvantages of the various methods used for assessing pharmacokinetics in critically ill patients with regard to specific aspects of pharmacokinetic research and further reviews data of selected antibiotics as examples for applications of the individual techniques.
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Use of Antiplatelet Therapy after Percutaneous Coronary Intervention with Bare-Metal Stents and Different Types of Drug-Eluting Stents
Authors: Tarunjit Singh, Linda Cuomo, Martin Cohen, Hasan A. Ahmad and Wilbert S. AronowDual antiplatelet therapy (DAPT) with a thienopyridine and aspirin has been the standard of care post coronary stent implantation. DAPT has been shown to reduce the risk of stent thrombosis (ST) and complications of myocardial infarction and death after placement of a drug-eluting stent (DES) and bare-metal stent (BMS).This article reviews the available clinical efficacy and safety data of antiplatelet therapies. The aim of this review is to highlight not only the importance of antiplatelets in the prevention of early and late thrombosis but also emphasize the importance of newer more potent antiplatelet agents and their role in the setting of clopidogrel resistance. MEDLINE, and EMBASE were searched for studies related to the clinical efficacy and safety of antiplatelet therapy after DES and BMS placement using the terms dual antiplatelet therapy, thienopyridine, aspirin, clopidogrel, prasugrel, ticagrelor,elinogrel, bare-metal stents, drug-eluting stent, stent thrombosis and myocardial infarction.
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The Intestinal Absorption Mechanism of Gabapentin Makes it Appropriate for Gastroretentive Delivery
Authors: Cuiping Chen, Verne E. Cowles and Michael SweeneyGabapentin is approved for the treatment of postherpetic neuralgia (PHN) and epilepsy. The pharmacokinetic (PK) properties of gabapentin, including absorption, distribution, metabolism, and excretion (ADME), were investigated during the development of Neurontin®, an immediate-release (IR) formulation of gabapentin that is orally administered three-times daily. Recently, a gastroretentive (GR) once-daily formulation of gabapentin (Gralise®) has been developed and marketed for the treatment of PHN. This review focuses on the ADME properties of gabapentin and illustrates how GR delivery enhances its absorption compared with IR formulations and allows once-daily dosing with the evening meal for the treatment of PHN. It includes the following aspects: 1) the mechanism of gastroretention of gabapentin GR tablets, 2) in vitro dissolution profiles of the GR and IR formulations, 3) site of absorption of gabapentin in the human intestine, 4) studies of the mechanism of gabapentin absorption using intestinal tissue preparations, 5) human PK studies to examine the effects of dose and formulations on PK profiles and the bioavailability of gabapentin at therapeutically relevant doses, and 6) efficacy and safety of gastroretentive gabapentin in patients with PHN. The data reviewed support that GR delivery of gabapentin optimizes its absorption via a saturable uptake mechanism. The prolonged residence of the GR tablets in the stomach coupled with the gradual release of gabapentin attenuates saturation of the transporter, thus enhancing absorption and increasing bioavailability, especially at therapeutically relevant doses. The net result is a once-daily formulation of gabapentin that is well tolerated and efficacious for the treatment of PHN.
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Neglected Aspects of Drug Discovery - Microbiological Aspects
Authors: Jacob Golenser and Nicholas HuntDeveloping new, efficient drugs is a long and costly process. However, although a failure to establish new drugs can in part be related to lack of funding, often it is also associated with various deficiencies in current approaches to drug development. Chemical and genetic validation, in addition to estimating future drug resistance, are considered critical for predicting the therapeutic efficacy of a compound. However, such approaches, when employed to decide upon further investigation or rejection of a candidate drug, often ignore several factors. These are: (i) the possibility of successful treatment by rejected drugs – compounds used in the past that individually are no longer effective because of resistance but are useful in combination; (ii) synergy between drugs that are not necessarily directed against the pathogen; (iii) drugs that can attenuate immune or inflammatory responses and consequently can alleviate clinical symptoms that are caused by host responses against the pathogen. High-throughput screening (HTS) could be adapted to accommodate these categories but, ultimately, only in vivo assessment would reveal really significant therapeutic effects. One group of investigators is unlikely to be able to complete the development of a drug, from idea to a successful product. However, individual efforts might contribute and be significant for the advance towards drug applicability.
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Phase I Clinical Trial of Exherin (ADH-1) in Patients with Advanced Solid Tumors
Authors: Nirit Yarom, David Stewart, Rajesh Malik, Julie Wells, Leonard Avruch and Derek J. JonkerADH-1 (Exherin™) is a pentapeptide, which competitively inhibits N-cadherin, resulting in vascular disruptive effect of tumor vasculature in preclinical models. This study was designed to assess the toxicity of ADH-1 and to determine the maximal tolerated dose (MTD). Patients and Methods: Adult patients with advanced measurable solid tumors were stratified according to their tumor N-cadherin status. ADH-1 was administered as a short infusion, every six weeks. Assessment of response was done every 6 weeks. PK parameters included: estimated volume of distribution of the central compartment, the α and β phase half-lives, area under the plasma concentration- time curve (AUC), clearance, and volume of distribution. Target lesions were assessed by dynamic contrast enhancing- magnetic resonance imaging (DCE-MRI). Results: 46 patients were enrolled, 25 (54%) had N-cadherin positive status. The doses administered ranged from 50 mg/m2 to 1000 mg/m2, and the MTD was not reached. The PK analysis of the concentration-time data displayed a biphasic profile. Most of the toxicities were grade 1 and 2 with fatigue, nausea, chest pain and dysgeusia being the most common. Eleven patients had disease control, the single patient who had partial response had N-cadherin positive tumor. Conclusion: ADH-1 is a well tolerated drug with a modest anti tumor effect in tumors which express N-cadherin.
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