Katie E. Cardone

Medication Reconciliation and Therapy Management in Dialysis-Dependent Patients: Need for a Systematic Approach

Patients with ESRD undergoing dialysis have highly complex medication regimens and disproportionately higher total cost of care compared with the general Medicare population. As shown by several studies, dialysis-dependent patients are at especially high risk for medication-related problems. Providing medication reconciliation and therapy management services is critically important to avoid costs associated with medication-related problems, such as adverse drug events and hospitalizations in the ESRD population. The Medicare Modernization Act of 2003 included an unfunded mandate stipulating that medication therapy management be offered to high-risk patients enrolled in Medicare Part D. Medication management services are distinct from the dispensing of medications and involve a complete medication review for all disease states. The dialysis facility is a logical coordination center for medication management services, like medication therapy management, and it is likely the first health care facility that a patient will present to after a care transition. A dedicated and adequately trained clinician, such as a pharmacist, is needed to provide consistent, high-quality medication management services. Medication reconciliation and medication management services that could consistently and systematically identify and resolve medication-related problems would be likely to improve ESRD patient outcomes and reduce total cost of care. Herein, this work provides a review of available evidence and recommendations for optimal delivery of medication management services to ESRD patients in a dialysis facility-centered model.

Medication-related Problems in CKD

Patients with CKD are often prescribed heterogeneous medications to treat disease-associated comorbidities, to slow down progression of the disease, and to minimize morbidity and mortality rates. However, the medication regimens of this population are very complex, leading to an increased potential for medication-related problems (MRPs). As kidney function declines, the type and amount of medications a patient consumes increases, thereby putting them at a higher risk for MRPs. MRPs have been known to be associated with morbidity, mortality, and a lower quality of life. This review will summarize data on the prevalence and effect of MRPs, and strategies that can be used by clinicians to reduce and resolve MRPs.

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.

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.

Ertapenem Pharmacokinetics and Pharmacodynamics during Continuous Ambulatory Peritoneal Dialysis

ABSTRACT Scant data exist for the pharmacokinetics (PK) of ertapenem in patients on continuous ambulatory peritoneal dialysis (CAPD). The goals of this study were to characterize the PK profile of ertapenem during CAPD, determine the extent of ertapenem penetration into the peritoneal cavity, and quantify the probability of the target attainment (PTA) profile in the serum and peritoneal cavity. A single-dose PK study was conducted in seven patients on CAPD. Population PK modeling and Monte Carlo simulation determined the probability that ertapenem at 500 mg intravenously (i.v.) every 24 h (q24h) would achieve concentrations in excess of the MIC for 40% of the dosing interval (40% T>MIC, where T is time) in the serum and peritoneal cavity. Monte Carlo simulation was also used to calculate the peritoneal cavity/serum mean and median penetration ratios by estimating the area under the concentration-time curve in the peritoneal cavity and serum (AUCPeritoneal and AUCSerum, respectively) from zero to infinity after a single simulated dose. The population mean (± standard deviation [SD]) values for the apparent volume in the central compartment, clearance, and apparent volume in the peritoneal cavity were 2.78 (0.62) liters, 0.24 (0.07) liters/hr, and 5.81 (2.05) liters, respectively. The mean (SD) AUCPeritoneal/AUCSerum ratio was 1.039 (0.861), and the median penetration ratio was 0.801 (interquartile range, 0.486 to 1.317). In both the serum and peritoneal cavity, ertapenem at 500 mg i.v. q24h was very likely (>90%) to achieve the pharmacodynamic target for MICs of ≤2 mg/liter. The simulations suggest that 500 mg of ertapenem i.v. q24h is very likely to achieve the exposure target associated with clinical efficacy in both the serum and peritoneal cavity against the range of MIC values deemed susceptible by the Clinical and Laboratory Standards Institute.

A Review of Phosphate Binders in Chronic Kidney Disease: Incremental Progress or Just Higher Costs?

As kidney disease progresses, phosphorus retention also increases, and phosphate binders are used to treat hyperphosphatemia. Clinicians prescribe phosphate binders thinking that reducing total body burden of phosphorus may decrease risks of mineral and bone disorder, fractures, cardiovascular disease, progression of kidney disease, and mortality. Recent meta-analyses suggest that sevelamer use results in lower mortality than use of calcium-containing phosphate binders. However, studies included in meta-analyses show significant heterogeneity, and exclusion or inclusion of specific studies alters results. Since no long-term studies have been conducted to determine whether treatment with any phosphate binder is better than placebo on any hard clinical endpoint (including mortality), it is unclear whether possible benefit with sevelamer represents net benefit of sevelamer, net harm with calcium-containing phosphate binders, or both. Although one meta-analysis suggested that calcium acetate may be more efficacious gram for gram than calcium carbonate as a binder, calcium acetate did not reduce hypercalcemia, and gastrointestinal intolerance was higher. Data are insufficient to determine whether calcium acetate provides lower risk of vascular calcification than calcium carbonate. Fears of lanthanum accumulation in the central nervous system or bone with long-term treatment do not appear to be warranted. Newer iron-containing phosphate binders have potential benefits, such as lower pill burden (sucroferric oxyhydroxide) and improved iron parameters (ferric citrate). The biggest challenge to phosphate binder efficacy is non-adherence. This article reviews the current knowledge regarding safety, effectiveness, and adherence with currently marketed phosphate binders and those in development.

Multidisciplinary views toward pharmacist-delivered medication therapy management services in dialysis facilities

OBJECTIVE To determine views of staff of dialysis centers toward pharmacist-delivered medication therapy management (MTM) services. DESIGN Focus group study. SETTING Three private, nonprofit, outpatient dialysis facilities. PARTICIPANTS Multidisciplinary dialysis staff. INTERVENTION Two focus group sessions were conducted using a semistructured interview guide. MAIN OUTCOME MEASURES Views of staff toward MTM services at a dialysis center. RESULTS A total of 13 staff members of dialysis centers participated in the study. Participants included nurses, patient care technicians, a social worker, dietitian, and administrative personnel. Key themes included: the need for access to MTM services in dialysis facilities exists; services should include medication reconciliation and patient education; services should be proactive, consistent, individualized, and covered by insurance; and that pharmacists are uniquely suited to provide MTM services. CONCLUSION Dialysis staff support the integration of MTM services in facilities. Further research is needed to identify barriers and opportunities in the implementation process, including patient perspectives.

Experiential Education Builds Student Self-Confidence in Delivering Medication Therapy Management

To determine the impact of advanced pharmacy practice experiences (APPE) on student self-confidence related to medication therapy management (MTM), fourth-year pharmacy students were surveyed pre/post APPE to: identify exposure to MTM learning opportunities, assess knowledge of the MTM core components, and assess self-confidence performing MTM services. An anonymous electronic questionnaire administered pre/post APPE captured demographics, factors predicted to impact student self-confidence (Grade point average (GPA), work experience, exposure to MTM learning opportunities), MTM knowledge and self-confidence conducting MTM using a 5-point Likert scale (1 = Not at all Confident; 5 = Extremely Confident). Sixty-two students (26% response rate) responded to the pre-APPE questionnaire and n = 44 (18%) to the post-APPE. Over 90% demonstrated MTM knowledge and 68.2% completed MTM learning activities. APPE experiences significantly improved students’ overall self-confidence (pre-APPE = 3.27 (0.85 SD), post-APPE = 4.02 (0.88), p < 0.001). Students engaging in MTM learning opportunities had higher self-confidence post-APPE (4.20 (0.71)) vs. those not reporting MTM learning opportunities (3.64 (1.08), p = 0.05). Post-APPE, fewer students reported MTM was patient-centric or anticipated engaging in MTM post-graduation. APPE learning opportunities increased student self-confidence to provide MTM services. However, the reduction in anticipated engagement in MTM post-graduation and reduction in sensing the patient-centric nature of MTM practice, may reveal a gap between practice expectations and reality.

Reevaluation of Ceftazidime Dosing Recommendations in Patients on Continuous Ambulatory Peritoneal Dialysis

ABSTRACT While intraperitoneal (i.p.) ceftazidime is commonly used to treat continuous ambulatory peritoneal dialysis (CAPD)-related infections, the ability of i.p. regimens to achieve critical pharmacodynamic targets in both blood and dialysate has not been reported. To understand the pharmacodynamic profile of ceftazidime during CAPD, data were obtained from a single-dose pharmacokinetic (PK) i.p. ceftazidime study that included 10 CAPD patients who received i.p. ceftazidime at 15 mg/kg of body weight. The probability of target attainment (concentrations maintained above the MIC for >60% of the dosing interval [60% T > MIC]) was determined for six simulated regimens. A 3-compartment model with each dialysis dwell modeled as a separate differential equation was fit to ceftazidime concentrations using BigNPAG. Embedded with the final PK model, serum and dialysate concentration-time profiles of ceftazidime at 1, 1.5, and 2 g i.p. every 24 h (q24h) to q48h were simulated using ADAPT 5. The mean population pharmacokinetic parameters were as follows: apparent volume of the central compartment (Vc), 7.57 liter; apparent volume of the peritoneal cavity (Vpd), 2.44 liter; clearance from the central compartment (CL), 0.379 liter/h; intercompartmental transfer rate constants (first order) between the central and peripheral compartments (k12 and k21), 4.66 and 4.88 h−1, respectively; and intercompartmental transfer rate constants (first order) between the central and peritoneal compartments (k13 and k31), 0.111 and 0.227 h−1, respectively. In serum, the probability of target attainment for MICs of ≤8 mg/liter exceeded 90% for 1.5 to 2 g i.p. q24h to q48h. However, no tested regimen provided adequate dialysate exposure at MICs of ≥8 mg/liter on day 1 without the use of a 3-g loading dose (post hoc analysis). On day 2, 1.5 to 2 g i.p. q24h or 2 g i.p. q48h provided adequate exposure in the peritoneal cavity. These results should be validated in the presence of infection. Ceftazidime i.p. at 1.5 or 2 g q24h to q48h is recommended for nonperitoneal infections. For peritonitis, a 3-g load with maintenance dosing of 1 to 2 g i.p. q24h or 2 g i.p. q48h is recommended.