Effects of Renal Function on Pharmacokinetics of Recombinant Human Granulocyte Colony-Stimulating Factor in Lung Cancer Patients

Animal studies suggest that the kidney is involved in the elimination of recombinant human granulocyte colony-stimulating factor (rhG-CSF), which is used for patients with neutropenia during cancer chemotherapy. Since anticancer drugs induce nephrotoxicity, it is important to clarify the role of the kidney in the pharmacokinetics of rhG-CSF in cancer patients. Our study was designed to evaluate the relationship between the pharmacokinetics of rhG-CSF and renal function in lung cancer patients compared to the absolute neutrophil count (ANC). The pharmacokinetic studies were conducted with 25 lung cancer patients. Following chemotherapy using platinum-based compounds, a bolus 5 microg of rhG-CSF/kg of body weight was intravenously injected from the first day of leukopenia or neutropenia. Pharmacokinetic parameters were estimated by fitting the concentration in serum-time data to a two-compartment model according to the population pharmacokinetics and the Bayesian method. Creatinine clearance (CL(CR)) was predicted by the Cockcroft-Gault formula. rhG-CSF clearance (CL(G-CSF)) correlated significantly with the ANC (r = 0.613; P < 0.001) and CL(CR) (r = 0.632; P < 0.001). Multiple linear regression analysis showed that the combination of the ANC and CL(CR) accounted for 57.4% of the variation of CL(G-CSF). In patients with an ANC of <1,000/microl, CL(CR) accounted for 72.9% of the variation of CL(G-CSF) (P < 0.001). Our findings suggest that renal function and neutrophil counts correlate with CL(G-CSF) and that the role of renal function in eliminating rhG-CSF is important in lung cancer patients with neutropenia.     

Potential adverse drug events in an indigent and homeless geriatric population.

OBJECTIVE: To identify potential adverse drug events (ADEs) in a geriatric ambulatory population using the modified Beers criteria. METHODS: This is a cross-sectional study of an indigent and homeless geriatric population served by a network of six primary healthcare clinics with clinical pharmacy services. Medical records of patients > or = 65 years old visiting the clinics between December 1999 and April 2000 were retrospectively reviewed by a clinical pharmacist. Medications meeting the modfied Beers criteria were evaluated for the most common drug classes involved, severity potential, and dose or disease state restrictions. Following the identification of medications meeting Beers criteria, the pharmacist left a written recommendation regarding use of alternative drugs or doses in the medical record. Physician acceptance of pharmacy recommendations was also evaluated. RESULTS: Medical records of 146 patients (71.9% women, average age 72.6 +/- 6.7 y) were reviewed. Overall, 52 patients (35.6%) had 70 medications with the potential for causing an ADE based on the modified Beers criteria The most commonly identified medication classes were narcotic analgesics (20.0%), antihypertensives (20.0%), and antihistamines (14.3%). Fifteen of these medications (21.4%) had a high severity potential. Identified medications met the following modified Beers criteria: 41.4% were inappropriate in a specific disease state, 38.6% were inappropriate for the elderly, 10.0% exceeded maximum dosage guidelines, and 10.0% were inappropriate for both the elerly and the patients disease state. Approximately 60% of pharmacy recommendations were accepted by physicians. CONCLUSIONS: The modified Beers criteria are a useful tool for reviewing medical records to identify potential ADEs in an ambulatory geriatric population.     

Discrepancies between medical and pharmacy records for patients on anti-HIV drugs

OBJECTIVE: To compare and evaluate drug notations in outpatient medical records and in pharmacy records in a cohort of HIV-1-infected patients treated with antiretroviral drugs. METHODS: Data on 103 patients were obtained from January 1, 1998, through December 31, 1999, by medical chart review and collection of pharmacy records. Two analyses were performed. First, antiretroviral drugs and comedication in the pharmacy records were documented and compared with their appearance in the outpatient medical records. Second, a detailed comparison was performed at 5 time points during the study period for the antiretroviral drugs. Generic name, formulation, strength, and frequency of dosing as registered in the outpatient medical records were compared with those registered in the pharmacy records. RESULTS: Total drug dispensation was 1607 (366 and 1241 antiretroviral drugs and comedication, respectively). The first screening resulted in a total discrepancy of 55.1% (n = 885), of which 97.1% (n = 859) was attributed to the comedication and 2.9% (n = 26) to the antiretroviral drugs. The discrepancy for the antiretroviral drugs at the specific time points ranged from 5.1% to 12.6% when the generic name only was used, and from 7.1% to 17% when formulation, strength, and frequency of dosing were also taken into account. CONCLUSIONS: The observed discrepancy between outpatient medical records and pharmacy records mainly concerns the comedication. For the antiretroviral drugs fewer, but still substantial, discrepancies were observed. These results indicate that full exchange of information conceming drug use in this population between general practitioners and specialists (infectious disease) is lacking.     

Prophylaxis of chemotherapy-induced febrile neutropenia with granulocyte colony-stimulating factors: where are we now?

Updated international guidelines published in 2006 have broadened the scope for the use of granulocyte colony-stimulating factor (G-CSF) in supporting delivery of myelosuppressive chemotherapy. G-CSF prophylaxis is now recommended when the overall risk of febrile neutropenia (FN) due to regimen and individual patient factors is ≥20%, for supporting dose-dense and dose-intense chemotherapy and to help maintain dose density where dose reductions have been shown to compromise outcomes. Indeed, there is now a large body of evidence for the efficacy of G-CSFs in supporting dose-dense chemotherapy. Predictive tools that can help target those patients who are most at risk of FN are now becoming available. Recent analyses have shown that, by reducing the risk of FN and chemotherapy dose delays and reductions, G-CSF prophylaxis can potentially enhance survival benefits in patients receiving chemotherapy in curative settings. Accumulating data from ‘real-world’ clinical practice settings indicate that patients often receive abbreviated courses of daily G-CSF and consequently obtain a reduced level of FN protection. A single dose of PEGylated G-CSF (pegfilgrastim) may provide a more effective, as well as a more convenient, alternative to daily G-CSF. Prospective studies are needed to validate the importance of delivering the full dose intensity of standard chemotherapy regimens, with G-CSF support where appropriate, across a range of settings. These studies should also incorporate prospective evaluation of risk stratification for neutropenia and its complications.     

Granulocyte colony-stimulating factor (G-CSF) patterns of use in cancer patients receiving myelosuppressive chemotherapy

Purpose

Febrile neutropenia (FN) is a common and serious complication of myelosuppressive chemotherapy. Guidelines recommend primary granulocyte colony-stimulating factors (G-CSF) prophylaxis (PPG) in patients with a high risk (HR, >20 %) of developing FN. We performed a retrospective analysis using a subset of the Medicare 5 % database to assess patterns of G-CSF use and FN occurrence among elderly cancer patients receiving myelosuppressive chemotherapy.

Methods

Chemotherapy courses for patients aged 65+?years were identified; only the first course was used for this analysis. Using clinical guidelines, chemotherapy regimens were classified as HR or intermediate risk (IR) for FN. The first administration of G-CSF was classified as either PPG (within the first 5 days of the first cycle), secondary prophylaxis, or reactive.

Results

Twelve thousand seven hundred seven courses across five tumor types were classified as having a HR or IR regimen. G-CSF was used in 24.5–73.8 % of patients receiving a HR FN regimen, with the highest use in breast cancer or NHL. Except for breast cancer (where PPG was used in 52.1 %), PPG was given in less than half of patients receiving a HR regimen. Depending on the tumor type, 4.8–22.6 % of patients with a HR regimen had a neutropenia-related hospitalization.

Conclusions

Guidelines recommend PPG with HR FN regimens and older age (>65 years), an important risk factor for developing severe neutropenic complications. However, our results show that in this elderly population, PPG was not routinely used (range 4.8–52.1 %) in patients receiving HR FN regimens. Careful attention to FN risk factors, including chemotherapy regimen and patient age, is needed when planning treatment strategies.     

Clinical efficacy of adjunctive G-CSF on solid tumor and lymphoma patients with established febrile neutropenia

Background

The use of granulocyte colony-stimulating factor (G-CSF) as a prophylaxis against febrile neutropenia (FN) is well documented in the literature; however, the therapeutic use of G-CSF in the treatment of FN remains controversial. This study assessed the efficacy of adjunctive G-CSF in the treatment of FN by evaluating clinical outcomes.

Methods

This was a single-center, prospective cohort study conducted at the National Cancer Center in Singapore. Adult patients who had received chemotherapy and developed FN between January 2009 and January 2012 were included in the analysis. The clinical efficacy of adjunctive G-CSF was evaluated by investigating the duration of hospitalization, duration to absolute neutrophil count (ANC) recovery, duration of grade IV neutropenia, duration to fever resolution, duration of antibiotic therapy, and incidence of documented infections. A multivariate analysis was performed to identify patients who could potentially benefit from adjunctive G-CSF.

Results

Four hundred and thirty patients were analyzed. Majority manifested low-risk FN (81.2 %) based on the Multinational Association of Supportive Care in Cancer (MASCC) scoring. Compared to patients who did not receive adjunctive G-CSF, patients receiving adjunctive G-CSF had a nonsignificant reduction in the duration of hospitalization (3.5 vs. 3.7 days, p?=?0.41) and in ANC recovery time (3.4 vs. 3.5 days, p?=?0.76). Neutropenia-related mortality was lower among those who have received adjunctive G-CSF (2.4 vs. 8.4 %, p?=?0.006). Patients of Indian ethnicity and those who underwent gemcitabine-containing chemotherapy were less likely to receive adjunctive G-CSF treatment.

Conclusions

This observational study suggested that adjunctive G-CSF may confer clinical benefits among solid tumor and lymphoma patients with established febrile neutropenia. Further research should be conducted to validate the findings.     

Racial differences in impact of coverage on diabetes self-monitoring in a health maintenance organization

BACKGROUND: Insurance coverage of patient self-management devices like self-monitoring blood glucose (SMBG) equipment may help to reduce race-related barriers to effective care. OBJECTIVES: We examined whether providing free home glucose monitors had greater impacts on self-monitoring among black versus white patients with diabetes. RESEARCH DESIGN: Using electronic medical record data (1992-1996), we used longitudinal survival analysis to examine racial differences in rates of initiation of SMBG after coverage and rates of discontinuation of SMBG 18 months after initiation. We used piecewise Cox models to compare relative rates of SMBG initiation between black and white patients before and after the policy. SUBJECTS: The study cohort included 2275 continuously enrolled adult patients with diabetes in a large, staff model HMO. Multivariate models were restricted to patients using oral therapy. RESULTS: Controlling for time-dependent and fixed effects, black patients were as likely to initiate SMBG as white patients before the policy (hazard ratio 1.14; 95% confidence interval 0.86-1.50) but more likely after the policy (hazard ratio 1.33; 95% confidence interval 1.01-1.76). Among postpolicy SMBG initiators, black patients were consistently at higher risk of SMBG discontinuation than white patients over time (P < 0.05). By the end of follow-up, discontinuation rates were 78% among black patients and 64% among white patients. CONCLUSIONS: The policy is effective in triggering additional diabetes patients to self-manage, particularly black patients. However, persistence after initiation of monitoring is short-lived. Although our results show the potential of such policies to narrow racial gaps in self-management among racial minority groups, further interventions may be needed to promote long-term adherence.     

Performance status of health care facilities changes with risk adjustment of HbA1c

OBJECTIVE: To develop a risk adjustment method for HbA1c, based solely on administrative data and to determine the extent to which risk-adjusted HbA1c changes the identification of high- or low-performing medical facilities. RESEARCH DESIGN AND METHODS: Through use of pharmacy records, 204,472 diabetic patients were identified for federal fiscal year 1996 (FY96). Complete information (HbA1c levels, demographic data, inpatient records, outpatient pharmacy utilization records) was available on 38,173 predominantly male patients from 48 Veterans Health Administration (VHA) medical facilities. Hierarchical mixed-effects models were used to estimate risk-adjusted unique facility-level HbA1c. RESULTS: Predicted HbA1c demonstrated expected patterns for major factors known to influence glycemic control. Poorer glycemic control was seen in minorities and patients with greater disease severity, longer duration of disease (using treatment type or presence of amputation as surrogates), and more extensive comorbidity (measured by an adapted Charlson index). Better glycemic control was seen in Caucasians, older diabetic patients, and patients with higher outpatient utilization. The number of performance outliers was reduced as a result of risk adjustment. For mean HbA1c levels, 7 facilities that were initially identified as statistically significant outliers were no longer outliers after risk adjustment. For high-risk HbA1c (>9.5%) rates, 12 facilities that were initially identified as statistically significant outliers were no longer outliers after risk adjustment. CONCLUSIONS: Risk adjustment using only administrative data resulted in substantial changes in identification of high or low performers compared with non-risk-adjusted HbA1c. Although our findings are exploratory, risk adjustment using administrative data may be a necessary and achievable step in quality assessment of diabetes care measured by rates of high-risk HbA1c (>9.5%).     

G－CSF对化疗后外周血干细胞动员作用的影响

通过对１１例急性白血病患者单独化疗与化疗后加用粒细胞集落刺激因子（Ｇ－ＣＳＦ）的对比，动态观察了Ｇ－ＣＳＦ对外周血造血干细胞（ＰＢＳＣ）的动员作用。发现化疗后加用Ｇ－ＣＳＦ比单用化疗的粒－巨噬细胞集落形成单位（ＣＦＵ－ＧＭ）增加５．１倍，红系爆式集落形成单位（ＢＦＵ－Ｅ）增加４．５倍。Ｇ－ＣＳＦ还可使ＣＦＵ－ＧＭ＞１００／ｍｌ和ＢＦＵ－Ｅ＞２００／ｍｌ的持续时间延长；化疗后ＣＦＵ－ＧＭ的最高值提早出现，而不影响ＢＦＵ－Ｅ／ＣＦＵ－ＧＭ比值。结果表明，化疗后加用Ｇ－ＣＳＦ可明显提高ＰＢＳＣ的收集效率，Ｇ－ＣＳＦ是一种有效的ＰＢＳＣ动员剂。     

Prospective drug utilization evaluation of three broad-spectrum antimicrobials: cefepime, piperacillin-tazobactam and meropenem

BACKGROUND: Cefepime, piperacillin-tazobactam and meropenem are among the broadest-spectrum and most expensive antimicrobials. AIM: To evaluate guidelines for appropriate use of these drugs. METHODS: We developed guidelines for use of these antibiotics, and conducted a two-phase drug utilization evaluation. We included all patients who received one of the study drugs during two 3-month periods, with an educational intervention in the intervening period. Appropriateness was determined for initiation of treatment, and for adaptation or continuation of established treatment. RESULTS: Overall, 205 patients received 271 courses with one of these antibiotics, for a total of 709 defined daily doses (DDD) of cefepime, 543 of piperacillin-tazobactam, and 680 of meropenem (8.3, 6.3 and 7.9 DDD/1000 admission days, respectively). Of these 271 courses, 234 were appropriate (86%). Treatment was continued for > or =5 days in 60%, of which 88% were appropriate (NS). Of the 271 courses, 210 (77%) were empirical (83% appropriate), while 61 (23%) were based on a relevant culture result (97% appropriate) (p < 0.001). Appropriateness differed significantly between departments (p < 0.001), and between the two phases (p < 0.001). The major difference between the two surveys was a decrease in meropenem usage (p < 0.05). DISCUSSION: The vast majority of courses with cefepime, piperacillin-tazobactam and meropenem are empirically selected and continued, underlying the importance of an optimal initial choice. Antibiotic guidelines, in conjunction with formal infectious disease consultation, can contribute to more appropriate use of these drugs.     

Granulocyte transfusion therapy in abdominal organ transplant recipients

Background: Patients with neutropenia are at increased risk for infections. Granulocyte transfusions (GT) have had mixed success in treatment of neutropenic infections in adult patients with hematologic malignancy. This study examined the outcomes of GT therapy in neutropenic solid organ transplant recipients, a novel population for this therapy. Methods: We performed a retrospective examination of the transfusion and medical records of all 14 solid organ‐transplant recipients without hematologic malignancy who experienced neutropenia and received GT therapy from 2004 to 2006. Results: Twelve patients received GT therapy for an active infection and two patients for infection prophylaxis. The mean absolute neutrophil count (ANC) one day increment per GT in these patients was 526/μl (median 215/μl). The mean ANC one day increment per dose of 10¹⁰ granulocytes was 246/μl (median 86/μl). Of the 12 infected patients, four patients (33%) showed a clinical response to GT with improvement or resolution of the infection, 7 (58%) patients had no clinical response and one additional patient had a clinical response to a course of GT but died during a second GT course. Neither patient receiving GT for prophylaxis developed an infection. Conclusions: We observed temporal increases in ANC to levels above 1,000/μl in 15/18 (83.3%) courses of GT. We observed a clinical response to infection in 5/12 (42%) patients, the remaining infected patients had no clinical response. Our results suggest that GT therapy in neutropenic solid organ transplant recipients can boost peripheral blood neutrophil counts. Additional studies areneeded to document an independent clinical benefit for GT in this patient population. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.     

Adherence to antidepressant treatment among privately insured patients diagnosed with depression

BACKGROUND: Antidepressants are effective in treatment of depression, but poor adherence to medication is a major obstacle to effective care. OBJECTIVE: We sought to describe patient and provider level factors associated with treatment adherence. METHODS: This was a retrospective, observational study using medical and pharmacy claims from a large health plan, for services provided between January 2003 and January 2005. We studied a total of 4312 subjects ages 18 or older who were continuously enrolled in the health plan with a new episode of major depression and who initiated antidepressant treatment. Treatment adherence was measured by using pharmacy refill records during the first 16 weeks (acute phase) and the 17-33 weeks after initiation of antidepressant therapy (continuation phase). Measures were based on Health Plan Employer Data and Information Set (HEDIS) quality measures for outpatient depression care. RESULTS: Fifty-one percent of patients were adherent through the acute phase; of those, 42% remained adherent in the continuation phase. Receipt of follow-up care from a psychiatrist and higher general pharmacy utilization (excluding psychotropics) were associated with better adherence in both phases. Younger age, comorbid alcohol or other substance abuse, comorbid cardiovascular/metabolic conditions, use of older generation antidepressants, and residence in lower-income neighborhoods were associated with lower acute-phase adherence. Continuation-phase adherence was lower for HMO participants than for others. CONCLUSION: In an insured population, many patients fall short of adherence to guideline recommended therapy for depression. Information from existing administrative data can be used to predict patients at highest risk of nonadherence, such as those with substance abuse, and to target interventions.     

Full-dose chemotherapy in early stage breast cancer regardless of absolute neutrophil count and without G-CSF does not increase chemotherapy-induced febrile neutropenia

Purpose

Does giving full-dose adjuvant chemotherapy to patients with early stage breast cancer (ESBC) regardless of the day-before absolute neutrophil count (ANC) lead to an increased incidence of chemotherapy-induced febrile neutropenia (CIFN)? What factors may predispose patients to CIFN?

Methods

This was a retrospective chart review conducted on all patients receiving adjuvant chemotherapy for ESBC at a mid-sized community hospital in Toronto, Ontario, Canada between September 2005 and August 2011. Day-before CBC data were collected along with other patient characteristics. CIFN was confirmed by hospital records. One hundred fifty-four patients met the inclusion criteria. Overall, 830 cycles of chemotherapy were analyzed. Univariate and multivariate logistic regression analyses were used to identify risk factors for CIFN.

Results

Twenty-two episodes of CIFN were observed. There was no significant difference in day-before ANC between patients who developed CIFN relative to those who did not. The day-before ANC was <1.5?×?10⁹/L for 88 cycles of chemotherapy. ANC analyzed as a continuous variable showed that the odds ratio (OR) for CIFN was 0.97 (95 % CI 0.82–1.13, p?=?NS). The pseudo R ² statistic, which is a measure of variability accounted for by a regression model, was only 0.0008, indicating that ANC explained less than 1 % of the variability in the risk of CIFN. The most significant predictor of CIFN was the chemotherapy regimen, with docetaxel (Taxotere)/cyclophosphamide demonstrating the highest risk (OR 7.1, 95 % CI 1.4–34.9, p?=?0.016).

Conclusions

Full-dose adjuvant chemotherapy may be given to patients with ESBC regardless of the day-before ANC, without significantly increasing the risk of CIFN. The chemotherapy regimen is the most significant predictor for CIFN.