Cefepime Precision Dosing Tool: from Standard to Precise Dose Using Nonparametric Population Pharmacokinetics.

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate a cefepime population pharmacokinetic (PK) model and integrate it into a precision dosing tool for implementation. Two data sets (680 patients) were used to build the cefepime PK model in Pmetrics, and three data sets (34 patients) were used for the validation. A separate application data set (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 h-1 (adults) and 0.96 h-1 (children), the central volume of distribution was 13.85 L, and the rate of transfer from the central to the peripheral compartments was 1.22 h-1 and from the peripheral to the central compartments was 1.38 h-1. After integration in BestDose, the observed versus predicted cefepime concentration fit using the application data set was excellent (R2 > 0.98), and the median difference between what was observed and what BestDose predicted on a second occasion was 4%. For the OID, cefepime at a 0.5- to 1-g 4-h infusion every 8 to 24 h (q8 to 24 h) with a CrCl of <70 mL/min was needed to achieve a target range of free trough:MIC 1 to 4 at a MIC of 8 mg/L, while continuous infusion was needed for higher CrCl and weight values. In conclusion, we developed and validated a cefepime model for clinical application. The model was integrated in a precision dosing tool for implementation, and the median concentration prediction bias was 4%. The OID algorithm was provided.

Virtually there: An innovative approach for training oncology pharmacy residents in gynecologic oncology.

OBJECTIVE: To develop an alternative approach to provide oncology pharmacy practice residents' education and training in the management of gynecologic malignancies in the absence of a specialist in this area at their institution. SETTING: Gynecologic oncology is a unique specialty in oncology. There is a need for more oncology clinical pharmacy specialists to participate in the care of patients with gynecologic malignancies as many do not have specific education in this area. PRACTICE DESCRIPTION: A virtual learning experience was developed that included all aspects of a typical experience with the exception of direct patient care. Postgraduate year 2 oncology pharmacy residents from 3 different programs were included. PRACTICE INNOVATION: Although the number of oncology clinical pharmacy specialists who are subspecialized in gynecologic oncology has grown, it is difficult to find experienced preceptors in gynecology oncology. We set to offer a virtual learning environment for programs that did not have a dedicated or highly specialized pharmacist in this area. EVALUATION: A pre- and postlearning assessment of the resident's knowledge of gynecologic malignancies was administered. Each trainee independently completed a validated 20-question gynecologic oncology knowledge assessment tool before and again after completion of all sessions. Midpoint and end-of-experience evaluations were completed via the phone with each resident. All evaluations were documented in PharmAcademic (McCreadie Group, Ann Arbor, MI), a required software program for postgraduate residency training programs. RESULTS: To date, 7 oncology pharmacy practice residents completed the virtual experience. A 42% improvement in scores pertaining to gynecologic oncology knowledge was identified. Residents were also satisfied with the overall virtual experience. Based on the assessment tool, all the residents gave positive evaluations with "always true" for 6 of the 7 questions. CONCLUSIONS: This pilot of a virtual experience was a successful platform to provide clinical knowledge and skills for oncology pharmacy residents in gynecologic oncology.

Assessment of bleeding incidences associated with rivaroxaban therapy in adults with solid tumors.

PURPOSE: Report bleeding incidences associated with rivaroxaban in adult patients with solid tumor malignancies requiring anticoagulation therapy. METHODS: This retrospective review was conducted at Indiana University Health, University Hospital and the Simon Cancer Center in Indianapolis, IN from January 2013 - February 2016. Patients were included if they had a solid tumor malignancy and prescribed rivaroxaban. Data were collected on 144 patients. Major bleeding was defined as bleeding requiring treatment (local, systemic treatment, blood cell transfusions) or hospitalization and minor bleeding was defined as bleeding not requiring treatment or hospitalization. RESULTS: Sixty-four (44%) patients experienced bleeding while on rivaroxaban. There were six cancer types that had a higher incidence of bleeding: bladder, breast, melanoma, pancreas, prostate, and renal cell cancers; 40% (6/15) of patients with bladder cancer experienced bleeding; 54% (7/13) with breast cancer experienced bleeding; 40% (4/10) of patients with melanoma experienced bleeding; 58% (11/19) of patients with pancreatic cancer experienced bleeding; 45% (10/22) of patients with prostate cancer experienced bleeding; and 56% (5/9) of patients with renal cell carcinoma experienced bleeding. No other data collected identified increased incidence of bleeding. CONCLUSIONS: Patients on rivaroxaban with a diagnosis of bladder, breast, melanoma, pancreas, prostate, or renal cell cancers had a higher incidence of bleeding compared to other solid tumors. Major bleeding was higher in bladder, breast, pancreas, and renal cell carcinomas, while minor bleeding was higher in patients with melanoma and prostate cancer.

Exceptional Response with Immunotherapy in a Patient with Anaplastic Thyroid Cancer.

Chemotherapy with or without radiation is the standard therapy for anaplastic thyroid cancer (ATC), although the response rate is not high and not durable. We describe a 62-year-old male who was diagnosed with ATC and initially treated with a thyroidectomy and lymph node dissection, followed by chemotherapy. Next generation sequencing was then performed to guide therapy and the tumor was found to have BRAF and programmed death-ligand 1 (PD-L1) positivity that was subsequently treated with vemurafenib and nivolumab. This led to substantial regression of tumor nodules. Genomic sequencing-based approaches to identify therapeutic targets has potential for improving outcomes. Currently, the patient continues to be in complete radiographic and clinical remission 20 months after beginning treatment with nivolumab. KEY POINTS: Programmed death-1 (PD-1)/PD-L1 immunotherapy has shown evidence of durable responses in certain malignancies such as melanoma, lung cancer, and renal cell carcinoma.PD-L1 positive tumors promote autoimmunity against the tumor; therefore, PD-1/PD-L1 blockade may be beneficial.Molecular profiling could possibly result in improved targeted therapy for certain malignancies.

Clinical Outcomes of a Pharmacy-Led Blood Factor Stewardship Program.

To report the results of a pharmacist-directed blood factor stewardship program targeting off-label utilization designed to limit use to established organizational guidelines in high-risk populations. Prospective evaluation of recombinant factor VIIa and prothrombin complex concentrate orders beginning June 2013 through May 2014 and a matched retrospective cohort from June 2012 to May 2013. Matched cohorts were evaluated for 28-day mortality, change in international normalized ratio (INR), adverse events, concurrent blood product use, and cost savings. Forty-two orders for blood factor were ordered between June 2013 and May 2014, 70 orders in the year before (N = 112). Twenty eight-day mortality was not different between the cohorts: 53.9% versus 50% (P = 0.77). Blood factor use with underlying liver failure and active bleeding was strongly associated with 28-day mortality: odds ratio (95% confidence interval), 2.9 (1.5-7.14) and 2.91 (0.01-2.91), respectively. Blood products dispensed increased over the year with plasma products the most significant (1 vs. 4 P = 0.004). All other clinical outcomes were nonsignificant. An annual cost savings of $375,539 was achieved, primarily through a significant reduction in recombinant factor VIIa and avoidance in high-risk patients. Use of off-label blood factors can be controlled through a pharmacist-led stewardship program. Twenty eight-day mortality was not different between the 2 cohorts; however, identification of risk factors for death associated with blood factor use allows for restriction in high-risk populations, creates a discussion of futile care, and yields cost savings.

Cyclophosphamide/fludarabine nonmyeloablative allotransplant for acute myeloid leukemia.

We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165 patients with acute myelogenous leukemia (AML) in remission or without frank relapse. Patients who received NMAT were more likely to be older and have secondary AML and lower performance status. At a median follow-up of 61 months, median event-free survival and overall survival survival were not different between NMAT and MAT in univariate as well as multivariate analyses. Cy/Flu NMAT may provide similar disease control and survival when compared with MAT in patients with AML in remission or without frank relapse.

Incidence of venous thromboembolism in the setting of hematopoietic cell transplantation.

The underlying risk of venous thromboembolism (VTE) is unclear in patients undergoing hematopoietic cell transplantation (HCT). As such, these patients should still be considered at risk for development of VTE due to factors such as their underlying malignancy and the marked inflammatory state that develops from treatment. The purpose of this study was to characterize the incidence of VTE in patients undergoing HCT. Retrospective chart review of patients from the Indiana University Stem Cell Transplant Unit treated between January 1, 2008, and May 24, 2011. Patients were older than 18 years and had undergone HCT. The primary objective was to analyze the incidence of VTE in patients undergoing autologous HCT versus allogeneic HCT. Secondary objectives included documentation of VTE treatment strategies and time to occurrence of VTE. Of the 567 patients who underwent autologous HCT, 14 developed VTE (2.5%), whereas 5 of the 180 patients who underwent allogeneic HCT developed VTE (2.8%; P = 1.000). The median time to development of VTE from admission for HCT was 12 days in the autologous HCT arm versus 19 days in the allogeneic HCT arm (P = 0.610). The most commonly used VTE treatment strategy was enoxaparin (12 out of 19 VTEs). This study illustrates that VTE does occur rarely in patients who have undergone HCT. The optimal treatment regimen in this population requires further evaluation. Until a reliable protocol for treatment and evidence for risk factors are established, providers should be vigilant for occurrence of VTE in these patients.

Prophylaxis with sirolimus and tacrolimus ± antithymocyte globulin reduces the risk of acute graft-versus-host disease without an overall survival benefit following allogeneic stem cell transplantation.

Methotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P = .160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P = .015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival.

Impact of an Oral Antineoplastic Renewal Clinic on Medication Possession Ratio and Cost-Savings.

PURPOSE: The primary objective of this study was to evaluate the impact of a pharmacist-driven oral antineoplastic (OAN) renewal clinic on medication adherence and cost savings. METHODS: This was a preimplementation and postimplementation retrospective cohort evaluation within a single US Department of Veterans Affairs health care system following implementation of a pharmacist-managed OAN refill clinic. The primary outcome was medication adherence defined as the median medication possession ratio (MPR) before and after implementation of the clinic. Secondary outcomes included the proportion of patients who were adherent from pre- to postimplementation and estimated cost-savings of this clinic. Patients were eligible for inclusion if they had received at least 2 prescriptions of the most commonly prescribed oral antineoplastic agents at the institution between September 1, 2013 and January 31, 2015. RESULTS: Of preimplementation patients, 96 of 99 (96.9%) were male and all patients (n = 35) in the postimplementation group were male. The mean age of the preimplementation group was 69.2 years while the postimplementation group was 68.4 years. Median MPR in the preimplementation group was 0.94, compared with 1.06 in the postimplementation group (P < .001). Thirty-six (36.7%) patients in the preimplementation group were considered nonadherent to their OAN regimen compared with zero patients in the postimplementation group. Estimated total cost savings was $36,335 in the postimplementation period. CONCLUSIONS: Implementation of a pharmacist-driven OAN renewal clinic was associated with a 12% increase in median MPR while saving an estimated $36,335 during the 5-month postimplementation period.

Peripheral blood stem cell mobilization tactics.

OBJECTIVE: To evaluate the methods and collection techniques currently used in stem cell mobilization for patients undergoing autologous transplantation. DATA SOURCES: Literature search was performed through PubMed (1948-August 2009) and MEDLINE (1977-August 2009). Reference citations from publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All literature identified was reviewed for inclusion. Original research and retrospective cohorts, along with previously published systematic reviews of stem cell mobilization and growth factors, were evaluated. Abstract data on plerixafor were also reviewed. DATA SYNTHESIS: Successful mobilization of an adequate number of progenitor cells can help ensure and improve time to neutrophil and platelet engraftment. A variety of methods have been studied to find the safest and most predictable mobilization of CD34+ progenitor cells, including use of single agents or the combinations of hematopoietic growth factors, chemotherapy, and a novel chemokine receptor 4 antagonist. Currently, granulocyte colony-stimulating factor (G-CSF) 10 microg/kg daily started 4 days prior to apheresis remains the standard of care for initial mobilization therapy. In patients who fail to mobilize or who are at high risk for mobilization failure, cyclophosphamide in conjunction with G-CSF may be used. Plerixafor, a novel chemokine receptor antagonist, in combination with G-CSF has demonstrated superiority for achieving collection goals compared to G-CSF alone in 2 Phase 3 trials. CONCLUSIONS: The optimal mobilization strategy is still unknown; however, colony-stimulating factors remain the most commonly used mobilization agents. Currently, chemotherapy or plerixafor in combination with G-CSF is a reasonable option in heavily pretreated and hard-to-mobilize patients with non-Hodgkin's lymphoma and multiple myeloma.

Precision Genomic Practice in Oncology: Pharmacist Role and Experience in an Ambulatory Care Clinic.

Recent advancements in molecular testing, the availability of cost-effective technology, and novel approaches to clinical trial design have facilitated the implementation of tumor genome sequencing into standard of care oncology practices. Current models of precision oncology practice include specialized clinics or consultation services based on a molecular tumor board (MTB) approach. MTBs are comprised of interprofessional teams of clinicians and scientists who evaluate tumors at the molecular level to guide patient-specific targeted therapy. The practice of precision oncology utilizing MTB-based models is an emerging approach, transforming precision genomics from a novel concept into clinical practice. This rapid shift in practice from cytotoxic therapy to targeted medicine poses challenges, yet brings exciting opportunities to clinical pharmacists practicing in hematology and oncology. Only a few precision genomics programs in the United States have a strong pharmacy presence with oncology pharmacists serving in leadership roles in research, interpreting genomic sequencing, making treatment recommendations, and facilitating off-label drug procurement. This article describes the experience of the precision medicine clinic at the Indiana University Health Simon Cancer Center, with emphasis on the role of the pharmacist in the precision oncology initiative.

ß-lactam dosing strategies: Think before you push.

OBJECTIVES: There has been interest in administering cefepime, a ß-lactam antibiotic, via intravenous push (IVP) as a means to improve time to first-dose antibiotic and reduce cost; however, the downstream impacts on antibiotic exposure and pharmacodynamic efficacy need to be further evaluated. METHODS: This study used a population pharmacokinetic model for cefepime and simulated exposures to predict the pharmacodynamic (PD) effect for cefepime regimens administered via IVP or 30-minute intermittent infusion in adults with different renal functions. FDA-approved adult dosages of 1-2 g every 8 or 12 hours were compared. This study aimed to compare the absolute difference in pharmacodynamic probability of target attainment (PTA) between IVP and intermittent infusion, defined as free cefepime concentrations above organism MIC for ≥ 70% of the time. RESULTS: At MICs of 0.25-0.5 mg/L, absolute differences in PTA were observed, with a reduction as great as 2.3% (89% to 86.7% for 30-minute intermittent infusion and IVP, respectively). At MICs of 1-4 mg/L, 30-minute intermittent infusion and IVP exhibited PTA differences as great as 5.4%, from 89.4% to 84%, respectively. At MICs of ≥8 mg/L, similar absolute differences existed; however, no regimen achieved a PTA >70%. Across renal function strata of 60, 100 and 140 mL/minute (within the same dosing group and MICs), better renal function lowered PTAs. CONCLUSIONS: Simulations demonstrated that IVP cefepime resulted in lower PTAs than traditional intermittent infusion among a subset of elevated MICs. Clinicians should exercise caution in IVP strategy, as unintended clinical consequences are possible.

Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy.

PURPOSE: Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action. PATIENTS AND METHODS: A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters. RESULTS: Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity. CONCLUSION: The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common.

Development of Population and Bayesian Models for Applied Use in Patients Receiving Cefepime.

BACKGROUND AND OBJECTIVE: Understanding pharmacokinetic disposition of cefepime, a ß-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment. METHODS: Multiple physiologically relevant models were fit to pediatric and adult subject data. To evaluate the final model performance, a withheld group of 12 pediatric patients and two separate adult populations were assessed. RESULTS: Seventy subjects with a total of 604 cefepime concentrations were included in this study. All adults (n = 34) on average weighed 82.7 kg and displayed a mean creatinine clearance of 106.7 mL/min. All pediatric subjects (n = 36) had mean weight and creatinine clearance of 16.0 kg and 195.6 mL/min, respectively. A covariate-adjusted two-compartment model described the observed concentrations well (population model R2, 87.0%; Bayesian model R2, 96.5%). In the evaluation subsets, the model performed similarly well (population R2, 84.0%; Bayesian R2, 90.2%). CONCLUSION: The identified model serves well for population dosing and as a Bayesian prior for precision dosing.

Pharmacokinetics of Basiliximab for the Prevention of Graft-versus-Host Disease in Patients Undergoing Hematopoietic Cell Transplantation with Minimal-Intensity Cyclophosphamide and Fludarabine.

STUDY OBJECTIVE: Basiliximab is an immunosuppressive monoclonal antibody used for rejection prevention following solid organ transplantation; the pharmacokinetics (PK) of basiliximab in this setting are known. Basiliximab may also be used for prophylaxis and treatment of graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic cell transplantation (HCT); however, the PK of basiliximab in this setting are not known. Clinical transplant providers expect variation in the volume of distribution and clearance after nonmyeloablative allogeneic transplantation (NMAT) compared with solid organ transplantation. Blood loss, organ site-specific antibody accumulation, and differences in blood product use during the two transplantation approaches may generate differences in basiliximab PK. Therefore, the objective of this study was to describe the PK of basiliximab after its addition to a minimally intense NMAT regimen, in conjunction with cyclosporine, for GVHD prophylaxis in patients with hematologic malignancies. DESIGN: Population PK analysis of a single-center, single-arm, phase II clinical trial. SETTING: Academic cancer research center. PATIENTS: Fourteen adults with hematologic malignancies (acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, myelofibrosis, or severe aplastic anemia) and undergoing NMAT with a fully HLA-matched (10 of 10 antigen matched) related or unrelated donor. MEASUREMENTS AND MAIN RESULTS: Basiliximab was used in conjunction with cyclosporine to deplete activated T cells in vivo as GVHD prophylaxis. We developed a novel competitive enzyme-linked immunosorbent assay (ELISA) method using recombinant interleukin-2 receptor alpha-chain (IL-2Ra) and a commercially available soluble sIL-2R ELISA kit to permit the quantification of serum basiliximab concentrations and characterization of the PK properties of the drug in this patient population. Using a nonlinear mixed effects model with NONMEM software, a one-compartment model with first-order elimination best described the PK, as covariate analysis using stepwise covariate modeling did not improve the base model. CONCLUSION: We suggest a one-compartment population model with first-order elimination to capture the PK profile for basiliximab for this patient population.

Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology.

The Clinical Laboratory Improvement Amendments of 1988 require that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a Clinical Laboratory Improvement Amendments-accredited laboratory. Because no known reference materials were available, existing DNA samples were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other Clinical Laboratory Improvement Amendments-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays.

Clinical management of thymoma patients.

Thymoma and thymic carcinomas are rare epithelial tumors that arise from the thymus gland. Current management depends on staging, with surgery being the mainstay of therapy for stages I and II disease. Combined modality therapy, including radiation and chemotherapy, is recommended for patients who have invasive and metastatic disease. Relapse has been documented decades after initial therapy with options for treating recurrent advanced stage disease. Prospective studies have been limited, and current studies aim to evaluate novel treatment options.