Donald F. Brophy

The Pharmacokinetics of Subcutaneous Enoxaparin in End‐Stage Renal Disease

Study Objective. To evaluate the pharmacokinetics of enoxaparin in end‐stage renal disease (ESRD), and determine if dosage reduction is necessary to maintain antifactor Xa activity concentrations within the therapeutic range.

Risk of Infection with Intravenous Iron Therapy

Objective: To review the potential risks of administering intravenous iron to patients with infection. Data Sources: Literature was accessed through MEDLINE (1977–June 2007) and Google Scholar, using the terms intravenous iron, iron sucrose, ferric gluconate, iron dextran, and infection. In addition, reference citations from publications identified were reviewed. Study Selection and Data Extraction: All English-language articles identified from the data sources were evaluated. Studies that provided data relevant to the objective were used, including in vitro and animal studies. Data Synthesis: The role of iron in bacterial growth and the pathophysiology of cellular immunity create legitimate, yet theoretical, concerns that active infection may be exacerbated by the administration of intravenous iron. Human data relating to this issue are limited. A few small, human studies in a population with chronic kidney disease suggest a possible increased risk of developing an infection associated with intravenous iron; however, prospective human data directly linking intravenous iron to exacerbation of existing infection or infection-related mortality are lacking. In vitro data suggest that increased transferrin saturation related to iron administration may result in polymorphonuclear leukocyte dysfunction and decreased inhibition of bacterial growth. Sparse animal data have linked intravenous iron therapy with morbidity and mortality in sepsis models. Conclusions: Despite the limited human data, careful consideration of risk versus benefit should be used when administering intravenous iron to patients with ongoing infection. Additional clinical data are needed to determine whether intravenous iron administration worsens outcomes of patients with infection.

The pharmacokinetics of enoxaparin do not correlate with its pharmacodynamic effect in patients receiving dialysis therapies.

The pharmacokinetics and pharmacodynamics of enoxaparin were studied in healthy volunteers and hemodialysis and peritoneal dialysis subjects. Antifactor Xa activity estimated the pharmacokinetics, whereas thrombin generation time (TGT) estimated the pharmacodynamics. Enoxaparin 1 mg/kg was given subcutaneously to all subjects. Antifactor Xa Amax and AUC0–12 were similar between groups, but the TGTmax was significantly greater in the dialysis groups (P = .001). The thrombin generation time remained significantly more prolonged throughout the 12‐hour study period, and there was a trend toward greater TGT AUEC0–12 for both dialysis groups (P = .07). Patients receiving hemodialysis had greater sensitivity to enoxaparin compared to the other groups. These results suggest that in dialysis patients, there may be accumulation of active heparin metabolites that are undetected by the antifactor Xa assay. Therefore, these subjects exhibit greater thrombin generation time prolongation despite similar antifactor Xa exposure. Further large‐scale studies are needed to corroborate the results of this exploratory pilot study.

Antifactor Xa activity correlates to thrombin generation time, platelet contractile force and clot elastic modulus following ex vivo enoxaparin exposure in patients with and without renal dysfunction

Summary.u2002 Antifactor Xa activity is the gold standard monitoring parameter for low molecular weight heparin (LMWH) derivatives. It is frequently measured in high‐risk populations, such as patients with renal dysfunction. Despite antifactor Xa monitoring, however, bleeding in renal dysfunction patients receiving LMWH remains a problem. This study determined the relationship between antifactor Xa activity and three novel coagulation monitoring parameters: thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM). This study also assessed the effect of renal dysfunction on these relationships. This was an ex vivo pharmacodynamic study of the relationship between antifactor Xa activity and TGT, PCF and CEM in subjects both with and without renal dysfunction. Thirty subjects completed this study (10 controls, 10 chronic kidney disease subjects, and 10 end‐stage renal disease subjects receiving hemodialysis). Blood samples obtained from participants were spiked with increasing enoxaparin concentrations (0.25, 0.5, 1.0 and 3.0u2003IUu2003mL−1). Samples were analyzed for TGT, PCF and CEM. The relationship between antifactor Xa activity and TGT, PCF and CEM was determined by Pearsons correlation. The effect of renal dysfunction on the relationship between antifactor Xa activity and TGT, PCF and CEM was determined by analysis of covariance. There is strong correlation between antifactor Xa activity and TGT, CEM and PCF. The presence of renal dysfunction significantly prolongs the TGT, and decreases the CEM relative to controls. These results suggest that patients with renal dysfunction have a greater pharmacodynamic response to LMWH, independent of the pharmacokinetics of LMWH.

Warfarin Resistance in a Patient with Short Bowel Syndrome

Drug therapy in short bowel syndrome can be complicated by inadequate or incomplete absorption of drugs in the small intestine. Many case reports claim that warfarin absorption is not affected by the syndrome. We treated a patient with oral warfarin for recurring deep vein thrombosis; up to 20 mg/day was administered with no increase in the international normalized ratio. Drug‐drug interactions that may prevent absorption, increase metabolism, or antagonize the effects of warfarin were ruled out. Intravenous lipid administration, which is anecdotally reported to precipitate warfarin resistance, may have contributed to the condition, but dosing was less frequent than in published reports. The most probable explanation of warfarin resistance is the reduced surface area for drug absorption secondary to surgical removal of the patients duodenum and gastrojejunostomy.

Thrombin generation time is a novel parameter for monitoring enoxaparin therapy in patients with end-stage renal disease

Summary.u2002 Background:u2002Patients with end‐stage renal disease (ESRD) who receive enoxaparin are at increased risk for adverse bleeding episodes. This phenomenon appears to occur despite judicious monitoring of antifactor Xa (aFXa) activity. Better monitoring parameters are needed to quantify the anticoagulant effects of enoxaparin in the ESRD population. Objectives:u2002The objective of this study was to determine the utility of using thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM) to monitor the degree of anticoagulation in ESRD subjects, and to compare these results to aFXa activity, the current gold‐standard monitoring parameter. Methods:u2002Eight healthy volunteers without renal dysfunction and eight ESRD subjects were enrolled into this study. Subjects received a single dose of enoxaparin 1u2003mgu2003kg−1 subcutaneously, and blood samples were obtained for the determination of aFXa activity, TGT, PCF and CEM at baseline, 4, 8, and 12u2003h postdose. Results:u2002Baseline, 4, 8, and 12‐h aFXa activity concentrations were not different between groups. However, the corresponding TGT at 8 and 12u2003h was significantly prolonged in the ESRD group (Pu2003=u20030.04, and Pu2003=u20030.008, respectively). The 4‐h peak TGT trended toward significance (Pu2003=u20030.06). There were no differences in PCF or CEM across time. Conclusions:u2002These data suggest that the parameter aFXa activity is a poor predictor of the anticoagulant effect of enoxaparin in patients with ESRD. Thrombin generation time appears to be more sensitive to the antithrombotic effects of enoxaparin in this population. Further large‐scale trials are needed to corroborate these data.

Darbepoetin Alfa Therapeutic Interchange Protocol for Anemia in Dialysis

BACKGROUND Erythropoiesis-stimulating proteins, such as erythropoietin alfa and darbepoetin alfa, have positively impacted anemia management. These medications improve patient outcomes and quality of life. Their costs, however, remain a major barrier for health systems. OBJECTIVE To evaluate the development, implementation, and cost-effectiveness of an inpatient therapeutic interchange protocol for erythropoiesis-stimulating proteins at a large, tertiary care, university-affiliated health system. METHODS Virginia Commonwealth University Health System (VCUHS) developed and implemented a therapeutic interchange program to convert therapy for all inpatients undergoing dialysis from erythropoietin alfa to darbepoetin alfa for treatment of chronic kidney disease–related anemia. An evaluation of the economic impact of this program on drug expenditures over a fiscal quarter (2003) was conducted using historical comparator data (2002). RESULTS Preliminary evaluation of the program demonstrated cost-savings and reduced drug utilization of erythropoiesis-stimulating proteins in hospitalized dialysis patients. For the first quarter of 2003 compared with the first quarter of 2002, VCUHS realized a cost-savings of nearly

Role of N-Acetylcysteine in the Prevention of Radiocontrast-Induced Nephropathy

10 000, which was related to the programs aggressive screening procedure. When these data were normalized for equal numbers of patients in each group receiving one of the drugs, the actual cost-savings was over

An in vivo-in vitro study of cefepime and cefazolin dialytic clearance during high-flux hemodialysis.

2000. These cost-savings are largely due to reduced utilization of these expensive biotechnology products with implementation of a dosing protocol. CONCLUSIONS VCUHS has successfully developed and implemented a darbepoetin alfa therapeutic interchange protocol for hospitalized dialysis patients. This has translated into reduced use of erythropoiesis-stimulating proteins, resulting in cost-savings for the health system.

Use and prescribing patterns for erythropoiesis-stimulating agents in inpatient and outpatient hospital settings.

OBJECTIVE: To examine the role of N-acetylcysteine (NAC) in the prevention of radiocontrast—induced nephropathy (RIN). DATA SOURCES: A literature search of MEDLINE (1966–December 2001) was performed using the following search terms: N-acetylcysteine, nephropathy, acute renal failure, and radiocontrast. STUDY SELECTION: Pertinent English-language animal and human studies were reviewed. DATA SYNTHESIS: Few small animal trials have demonstrated that NAC significantly prevents the development or reduces the severity of acute renal failure. Two human studies demonstrated NAC significantly reduces the occurrence of RIN. CONCLUSIONS: NAC may reduce the occurrence of RIN in high-risk patients. Further large-scale studies are needed to corroborate findings from earlier trials.