Darren W. Grabe

Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)

Drug dosage adjustment for patients with acute or chronic kidney disease is an accepted standard of practice. The challenge is how to accurately estimate a patients kidney function in both acute and chronic kidney disease and determine the influence of renal replacement therapies on drug disposition. Kidney Disease: Improving Global Outcomes (KDIGO) held a conference to investigate these issues and propose recommendations for practitioners, researchers, and those involved in the drug development and regulatory arenas. The conference attendees discussed the major challenges facing drug dosage adjustment for patients with kidney disease. In particular, although glomerular filtration rate is the metric used to guide dose adjustment, kidney disease does affect nonrenal clearances, and this is not adequately considered in most pharmacokinetic studies. There are also inadequate studies in patients receiving all forms of renal replacement therapy and in the pediatric population. The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. The KDIGO Conference highlighted the gaps and focused on crafting paths to the future that will stimulate research and improve the global outcomes of patients with acute and chronic kidney disease.

Determination of iron sucrose (Venofer) or iron dextran (DexFerrum) removal by hemodialysis: an in-vitro study

BackgroundIntravenous iron is typically administered during the hemodialysis (HD) procedure. HD patients may be prescribed high-flux (HF) or high-efficiency (HE) dialysis membranes. The extent of iron sucrose and iron dextran removal by HD using HF or HE membranes and by ultrafiltration rate (UFR) is unknown.MethodsTwo in vitro HD systems were designed and constructed to determine the dialyzabiltiy of iron from a simulated blood system (SBS) containing 100 mg iron sucrose or iron dextran (system A) or 1000 mg iron sucrose (system B). Both in vitro systems utilized a 6-L closed-loop SBS system that was subject to 4 different HD conditions conducted over 4 hours: HE membrane + 0 ml/hr UFR; HE membrane + 500 ml/hr UFR; HF membrane + 0 ml/hr UFR; HF membrane + 500 ml/hr UFR. Blood flow and dialysate flow rates were 500 ml/min and 800 ml/min, respectively. The dialysate compartment was a 192-L open system for system A and a 6-L closed-loop system for system B. Samples from the SBS and dialysate compartments were taken at various time points and iron elimination rate and HD clearance was determined. Iron removal from the SBS > 15% was considered clinically significant.ResultsThe greatest percentage removal from the SBS was 13.5% and -0.03% utilizing system A and B, respectively. Iron sucrose and iron dextran dialysate concentration was below the lower limits of assay (< 2 ppm) for system A. Dialysate recovery of iron was negligible: 0 – 5.4 mg system A and 5.47 – 23.59 mg for system B. Dialyzer type or UFR did not affect iron removal.ConclusionHF or HE dialysis membranes do not remove clinically significant amounts of iron sucrose or dextran formulations over a 4-hour HD session. This effect remained constant even controlling for UFR up to 500 ml/hour. Therefore, iron sucrose and iron dextran are not dialyzed by HE or HF dialysis membranes irrespective of UFR.

Pharmacokinetics of intermittent intraperitoneal ceftazidime

Ceftazidime is currently recommended as an alternative first-line agent in the treatment of peritonitis and for Pseudomonas peritonitis. The pharmacokinetics of intermittent intraperitoneal (i.p.) ceftazidime have been poorly characterized. This study was designed to characterize the pharmacokinetic disposition of a single dose of ceftazidime in anuric and non-anuric CAPD patients, over 48 hours. This was a prospective, open label, pharmacokinetic study. The study was conducted in an independent, outpatient dialysis center. Ten volunteer continuous ambulatory peritoneal dialysis (CAPD) patients with and without residual renal function, no peritonitis or antibiotics in the previous 4 weeks, and on CAPD for at least 2 months were recruited. Patients received a single dose of i.p. ceftazidime (15 mg/kg) in the first daytime exchange over a 6-hour dwell, after an overnight dwell. Serum, urine, and dialysate were collected over a 48-hour period. A high-pressure liquid chromatography (HPLC) assay was used to analyze ceftazidime in these samples. Pharmacokinetic parameters were calculated. Six of the 10 patients were non-anuric with a mean residual renal creatinine clearance of 2.9 +/- 1.6 mL/min. The mean +/- SD bioavailability was 72% +/- 14%, and the volume of distribution was 0.34 +/- 0.08 L/kg. The mean serum elimination half-life of 22 +/- 5 hours. The peritoneal clearance was 5.74 +/- 1.6 mL/min. No difference was detected between anuric and nonanuric patients. Mean plasma and dialysate concentrations at 24 hours were 24 +/- 6 microg/mL and 18 +/- 7 microg/mL, respectively, and were 12.0 +/- 3.6 microg/mL and 7.4 +/- 3.1 microg/mL at 48 hours, respectively. Once-daily i.p. dosing of ceftazidime achieves serum and dialysate levels greater than the MIC of sensitive organisms over 48 hours.

Caring for Patients with Chronic Kidney Disease: A Joint Opinion of the Ambulatory Care and the Nephrology Practice and Research Networks of the American College of Clinical Pharmacy

An increasing number of patients are developing chronic kidney disease (CKD). Appropriate care for patients with CKD must occur in the earliest stages, preferably before CKD progresses to more severe stages. Therefore, recognition and treatment of CKD and its associated complications must occur in primary care settings. Patients with CKD often have comorbid conditions such as diabetes mellitus, hypertension, and dyslipidemia, creating specific considerations when treating these diseases. Also, these patients have CKD‐related conditions, including anemia and renal osteodystrophy, that are not traditionally evaluated and monitored by the primary care practitioner. Collectively, many opportunities exist for pharmacists who practice in the primary care setting to improve the care of patients with CKD.

Cefazolin dialytic clearance by high-efficiency and high-flux hemodialyzers

Cefazolin dialytic clearance has not been determined in patients undergoing hemodialysis with high-efficiency or high-flux dialyzers. The objective of this study is to determine the pharmacokinetics and dialytic clearance of cefazolin and develop dosing strategies in these patients. Twenty-five uninfected subjects undergoing chronic thrice-weekly hemodialysis were administered a single dose of intravenous cefazolin (15 mg/kg) after their standard hemodialysis session. Fifteen subjects underwent hemodialysis with high-efficiency hemodialyzers, and 10 subjects underwent hemodialysis with high-flux hemodialyzers. Blood and urine samples were collected serially over the interdialytic period, during the next intradialytic period, and immediately after the next hemodialysis session. Serum and urine concentrations of cefazolin were determined by high-performance liquid chromatography. Differential equations describing a two-compartment model were fit to the cefazolin serum concentration-time data over the study period, and pharmacokinetic parameters were determined. Mean dialytic clearance values for cefazolin were significantly greater in the high-flux group compared with the high-efficiency group (30.9 +/- 6.52 versus 18.0 +/- 6.26 mL/min, respectively; P: < 0.05). Cefazolin reduction ratios were significantly greater (0.62 +/- 0.08 versus 0.50 +/- 0.07; P: < 0.005) in the high-flux group compared with the high-efficiency group and correlated well with equilibrated urea reduction. The pharmacokinetic model developed from patient data was used to simulate cefazolin serum concentration data for high-efficiency and high-flux dialyzers. Cefazolin doses of 15 or 20 mg/kg after each hemodialysis session maintained adequate serum concentrations throughout a 2- or 3-day interdialytic period regardless of hemodialyzer type.

Use of Pharmacokinetic and Pharmacodynamic Principles To Determine Optimal Administration of Daptomycin in Patients Receiving Standardized Thrice-Weekly Hemodialysis

ABSTRACT This study identified optimal daptomycin dosing for patients receiving thrice-weekly hemodialysis (HD). Twelve adult patients on HD received daptomycin at 6 mg/kg of body weight intravenously (i.v.) one time; plasma and dialysate samples were collected over 3 days. A 2-compartment model with separate HD and non-HD clearance terms was fit to the data. A series of 9,999-subject Monte Carlo simulations (MCS) was performed to identify HD dosing schemes providing efficacy and toxicity profiles comparable to those obtained for MCS employing the daptomycin population pharmacokinetic (PK) model derived from patients in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. For efficacy, we selected the HD dosing scheme which generated an area-under-the-curve (AUC) exposure profile comparable to that for the SAB-IE population model. For toxicity, we selected HD dosing schemes that minimized trough concentrations of ≥24.3 mg/liter. Separate HD dosing schemes were developed for each FDA-approved regimen and for two weekly interdialytic periods (48 and 72 h). Administration of the same parent daptomycin dose intra-HD and post-HD resulted in AUC, maximum concentration of drug in serum (C max), and C min values most comparable to those for SAB-IE simulations for the 48-hour interdialytic period. In contrast, all candidate HD dosing schemes provided AUC48-72 values that were at least 50% lower than the SAB-IE AUC48-72 values. Increasing the parent dose by 50% provided more comparable AUC48-72 values while maintaining acceptable C min values. Administration of the daptomycin parent dose intra-HD or post-HD was optimal for the 48-h interdialytic period. For the 72-h interdialytic period, clinicians should consider increasing the dose by 50% to achieve more comparable AUC48-72 values.

Quantifying home medication regimen changes and quality of life in patients receiving nocturnal home hemodialysis

Medication regimen simplification may improve adherence in end‐stage kidney disease. The effect of nocturnal home hemodialysis (NHHD) on medication burden is unknown. A retrospective pilot study of NHHD patients was conducted. Medication information was collected at baseline, NHHD start, and at 3, 6, 12, 18, and 24 months. SF‐36 scores were collected at baseline, 6, 12, and 24 months. The number of medications, pill burden, and number of administrations per day were determined. Medication Regimen Complexity Index was used at each time point as a comparator. Medications for anemia, mineral and bone disorders (MBD), cardiovascular (CV) disease, infection, and vitamins were analyzed for number of medications and pill burden. Thirty‐five patients were included. Patients used 10.5 ± 4.4 medications at baseline and 11.8 ± 4.7 at the end of the study (P=NS). Regarding the number of medications, anemia medications, anti‐infectives, and vitamins increased; MBD and CV medications decreased by the end of the study. Total pill burden did not change over 24 months, nor did anemia pill burden. Mineral bone disorder and CV pill burden decreased, and vitamins and anti‐infective pill burden increased. Daily medication administration times decreased significantly from 5.0 ± 1.5 to 3.6 ± 1.5 by 24 months. Switching to NHHD was associated with a significant increase in Medication Regimen Complexity Index at 24 months (P<0.05). SF‐36 scores increased significantly once patients began on NHHD. No measure of medication regimen complexity was correlated with the SF‐36 score. Medication burden changes over time after starting NHHD. It is unknown what effect NHHD has on adherence or medication costs, and warrants further study in a prospective comparative investigation.

Development of an Immunoassay for Monitoring the Levels of Ciprofloxacin Patient Samples

It has been traditional to measure drug concentrations using high pressure liquid chromatography (HPLC). While this method is highly accurate, it is time consuming and requires the use of appropriate standards for identification of the compound. In addition, identification and quantification of drugs from patient samples requires significant manipulation to remove protein. In contrast, enzyme-linked immunoassays (EIA) are able to assay samples with a high degree of specificity, and are able to process multiple samples at a time. In addition, serum proteins do not interfere with sample quantification and samples may be tested without significant preparation. We describe the development of an EIA for the detection of ciprofloxacin in serum and dialysate samples. The immunoassay is specific for ciprofloxacin and is sensitive for picogram amounts of the antibiotic.

Comparison of Natural Product Use Between Primary Care and Nephrology Patients

BACKGROUND: The use of natural products is increasing, but healthcare professionals may underestimate the use of these agents by patients. It is unknown whether natural product use differs between primary care and specialty clinic patients, such as those in a nephrology clinic. OBJECTIVE: To compare patterns of natural product use between primary care and nephrology clinic patients. METHODS: One thousand adult patients from each clinic were randomly mailed an anonymous questionnaire to determine current and past use of natural products. RESULTS: A total of 491 surveys were returned, for an overall response rate of 26% (25% primary care; 28% nephrology clinic). Current use of natural products was similar between the primary care and nephrology groups (34% vs 29%, respectively; p = NS). Primary care patients were more likely to have taken a natural product in the past (57% vs 45%; p < 0.05); Echinacea was the most common product taken by those patients (26%). Green tea was the most common natural product taken by nephrology clinic patients (18%). More primary care patients took Echinacea compared with nephrology clinic patients (26% vs 12%; p < 0.01). Adverse reactions led to discontinuation of the natural product in 7% of respondents. CONCLUSIONS: Active use of natural products was similar between the survey respondents. Documentation and monitoring of natural product use by healthcare professionals working with primary care and nephrology clinic patients are recommended.

Daptomycin Pharmacokinetics and Pharmacodynamics in a Pooled Sample of Patients Receiving Thrice-Weekly Hemodialysis

ABSTRACT While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia–infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC48–72) that were <50% of the SAB-IE AUC48–72 values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC48–72 values, while maintaining acceptable trough concentration (Cmin) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for Cmin reaching ≥24.3 mg/liter were observed in one of the three studies. Given the high probability of Cmin being ≥24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.