Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin.

We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.

Improved Adherence Rates and Clinical Outcomes of an Integrated, Closed-Loop, Pharmacist-Led Oral Chemotherapy Management Program.

PURPOSE: To address the growing use of oral anticancer therapy, an integrated, closed-loop, pharmacist-led oral chemotherapy management program was created within an academic medical center. METHODS: An integrated, closed-loop, pharmacy-led oral chemotherapy management program was established. From September 2014 until June 2015, demographic information, rates of adherence, patient understanding of treatment, pharmacist interventions, patient and provider satisfaction, and molecular response rates in patients with chronic myeloid leukemia (CML) were collected. RESULTS: After full implementation, 107 patients were enrolled in our oral chemotherapy management program from September 2014 until June 2015. All patients were educated before starting oral chemotherapy, and using pre- and postassessment tests, comprehension of oral chemotherapy treatment increased from 43% to 95%. Patient-reported adherence was 86% and 94.7% for the GI/breast and malignant hematology patient populations, respectively, and these were validated with medication possession ratio, revealing adherence rates of 85% and 93.9% for the GI/breast and malignant hematology patient populations, respectively. A total of 350 encounters with a clinical pharmacist and 318 adverse effects were reported, which led to 235 interventions. This program led to a higher major molecular response rate (83%) in our CML population compared with published clinical trials (average major molecular response rates, 40% and 60% with 1- and 2-year follow-up, respectively). CONCLUSION: An innovative model was developed and resulted in improved patient knowledge regarding oral chemotherapy, improved adherence rates that exceeded nationally established thresholds, and superior major molecular response outcomes for patients with CML compared with published literature. As a result, this model has produced the gold standard in managing patients receiving oral chemotherapy.

Synthesis of a Selective Estrogen Receptor Degrader via a Stereospecific Elimination Approach.

An efficient synthesis of a selective estrogen receptor degrader, GDC-0810, bearing a challenging stereodefined (E)-tetrasubstituted all-carbon olefin core, is reported. The described synthetic route involves a highly diastereoselective addition of an arylmagnesium reagent 3a to ketone 4, yielding the key tertiary alcohol 2a in >99:1 dr. The corresponding tert-butyl carbonate derivative was identified among other leaving groups to provide the desired olefin geometry in a 98:2 E/Z ratio via a concerted elimination. A four-step telescoped process was then developed starting from the tertiary alcohol 2a to produce GDC-0810 API as a pyrrolidine salt in 70% yield.

Implementation of a longitudinal early immersion student pharmacist health system internship program.

PURPOSE: The initiation, implementation, and benefits of a longitudinal early immersion student pharmacist health system internship are described. EDUCATIONAL ACTIVITY: A two-year longitudinal internship experience was implemented to provide exposure into distributional operations, direct patient care activities, and health-system pharmacy administration. The intent of the program was to create an opportunity for student pharmacists to enhance the quality of their education with practical experience by immersing them early in their careers within the healthcare system. Early in their academic training the student interns were exposed to a broad range of services and programs while contributing longitudinally to the service line through quality improvement projects and distributional operations. The first year primarily focuses on distributional operations with direct patient care shadowing, while the second year targets intern involvement in hematology/oncology direct patient care activities. In this role, they are able to serve as pharmacist extenders. SUMMARY: Our comprehensive, longitudinal two-year health-system pharmacy internship program offers student pharmacists a unique early immersion experience that builds upon itself throughout their didactic training but is outside of the academic requirements. Students are exposed to distributional operations, direct patient care activities, and health system pharmacy administration prior to APPE rotations.

Implementation of an integrated pharmacy supply management strategy.

PURPOSE: Implementation of an integrated pharmacy supply management strategy is described. SUMMARY: In 2011, the formulary approval process and supply management for oncology medications were independent of each other at an oncology infusion center. Numerous nonformulary medications were kept on hand and reordered based on inventory levels that were established with inadequate usage information, while some formulary agents did not have on-hand inventory levels and had to be reordered on a patient-specific basis, which required paperwork and then a review by drug information staff per institutional policy. Because there was no true distinction in the ordering of formulary versus nonformulary oncology agents, the medical staff prescribed both in the same manner, leaving the pharmacy staff responsible for ensuring that enough quantities were on hand for many drugs, regardless of formulary status. Using supply chain management principles, a formal analysis of the on-hand inventory was performed. In addition, the formulary process for oncology drugs was restructured to align with how oncology drugs are managed for on-hand inventory levels. The alignment of these processes allowed the operation to have 1 supply strategy for the ambulatory oncology infusion center. As a result, inventory exhaustion rates were reduced by 70% and inventory turn rates improved by 78%. There was also significant time savings in the operational process streamlining, eliminating the rework and inefficiencies caused by an unclear process that was not fully captured in this assessment. CONCLUSION: Alignment of the formulary review process with inventory analyses that support supply management principles reduced inventory exhaustion while improving inventory turn rates.

Expanding care through a layered learning practice model.

PURPOSE: The outcomes of a patient-centered layered learning practice model (LLPM) in which the clinical specialist acted as the attending pharmacist and managed a pharmacy team to provide direct patient care were evaluated. METHODS: Two 30-day evaluations were conducted on the acute care malignant hematology and medical oncology services of the University of North Carolina Medical Center in 2011. The primary objective of this study was to design an LLPM that used a team to expand the pharmacist care services offered. The primary outcome was the frequency of pharmacy team encounters at discharge (medication reconciliation and counseling), termed the discharge capture rate. RESULTS: During the study months, 42 and 78 malignant hematology and medical oncology patients were eligible for study inclusion, respectively. The overall discharge capture rate was 51%. Sixty-one patients received discharge medication reconciliation services during patient counseling. Patients included in the malignant hematology group received a mean of 11 prescriptions at discharge, compared with 9.83 in the medical oncology group. Means of 1.26 and 2.1 medication-related problems per patient were identified in the malignant hematology and medical oncology studies, respectively, during discharge medication reconciliation. The overall mean face time spent per patient was 21.3 minutes. CONCLUSION: Patients in malignant hematology and medical oncology services were counseled and provided discharge medication reconciliation by a pharmacy student or resident whose activities were managed and reviewed by an attending pharmacist using an LLPM, resulting in an improvement in all clinical outcomes and measures.

Assessment of final product dosing accuracy when using volumetric technique in the preparation of chemotherapy.

BACKGROUND: Studies have compared gravimetric and volumetric dosing accuracies in chemotherapy agents, finding high accuracy in gravimetric measurements with a mean deviation of ± 0.06%, while volumetric measurements had a mean deviation of ± 3.02%. METHODS: Chemotherapy doses prepared under a biological safety cabinet containing two weights from the precision scale between 15 December 2010 and 30 March 2011 were eligible for inclusion. Empty syringes attached to a closed-system transfer device were weighed prior to product manipulation. The product was then prepared using the syringe pull-back method (volumetric technique) and the same syringe containing drug was weighed (gravimetric method). RESULTS: A total of 1156 compounded sterile products were eligible for the study. The mean percent volume difference of preparations included was -0.53% with a range of -64.9% to 94.22% for individual doses. Of the prepared doses, 71.7% were within ± 5% and 87.4% were within ± 10% of the ordered dose. Secondary outcomes found to be associated with an increased percent volume difference were the pediatric population, smaller volumes prepared, drugs requiring reconstitution compared to already in solution, and final product dispensed to the patient in syringes. CONCLUSION: While the mean value of volumetric measurements is within the generally understood acceptable range for dispensing chemotherapy, the range of measurements is highly variable. Future studies are warranted to better understand the reasons behind the variation and to evaluate the impact of workflow changes on improving final product accuracy.

Pharmacy-Initiated Transitions of Care Services: An Opportunity to Impact Patient Satisfaction.

PURPOSE: A transitions of care program at an academic teaching hospital was designed to reengineer the fragmented discharge process. The team included a pharmacy technician, called a transition specialist, who coordinated the medication needs of discharging patients. This study intends to assess the impact of the transitions of care program on patient satisfaction scores. METHODS: Two datasets of Press Ganey and Hospital Consumer Assessment of Healthcare Providers (HCAHPS) were analyzed. Patients eligible for inclusion were age 18 years or older and successfully discharged from the study facility. All participants received usual care by a servicebased pharmacist, medication counseling by a nurse prior to discharge, and other standard of care services by the inpatient medical team. The intervention group received the previously stated usual care plus services by the transitions of care program. RESULTS: The results from HCAHPS scores proved inconclusive. The results from the Press Ganey dataset found that the surgery transplant service demonstrated statistically significant improvement for satisfaction scores, and they warrant further review. CONCLUSIONS: Results demonstrate that HCAHPS metrics do not correlate with the successes or lack thereof of the transitions of care program. Press Ganey might be a potential surrogate marker for assessing the impact of this program. This study is the first to qualitatively evaluate pharmacy transitions of care service using patient satisfaction scores.

Economic and microbiologic evaluation of single-dose vial extension for hazardous drugs.

PURPOSE: The update of US Pharmacopeia Chapter <797> in 2008 included guidelines stating that single-dose vials (SDVs) opened and maintained in an International Organization for Standardization Class 5 environment can be used for up to 6 hours after initial puncture. A study was conducted to evaluate the cost of discarding vials after 6 hours and to further test sterility of vials beyond this time point, subsequently defined as the beyond-use date (BUD). METHODS: Financial determination of SDV waste included 2 months of retrospective review of all doses prescribed. Additionally, actual waste log data were collected. Active and control vials (prepared using sterilized trypticase soy broth) were recovered, instead of discarded, at the defined 6-hour BUD. RESULTS: The institution-specific waste of 19 selected SDV medications discarded at 6 hours was calculated at $766,000 annually, and tracking waste logs for these same medications was recorded at $770,000 annually. Microbiologic testing of vial extension beyond 6 hours showed that 11 (1.86%) of 592 samples had one colony-forming unit on one of two plates. Positive plates were negative at subsequent time points, and all positives were single isolates most likely introduced during the plating process. CONCLUSION: The cost of discarding vials at 6 hours was significant for hazardous medications in a large academic medical center. On the basis of microbiologic data, vial BUD extension demonstrated a contamination frequency of 1.86%, which likely represented exogenous contamination; vial BUD extension for the tested drugs showed no growth at subsequent time points and could provide an annual cost savings of more than $600,000.

Method to determine allocation of clinical pharmacist resources.

PURPOSE: An objective methodology to guide decisions by hospital pharmacy departments on the best use of clinical pharmacist personnel is described. SUMMARY: To help determine the optimal deployment of state-licensed Clinical Pharmacist Specialist (CPS) staff, a task force led by the pharmacy department at University of North Carolina (UNC) Hospitals developed an objective approach to evaluating the relative need for and potential impact of CPS expertise within the medical center's many service units. After analyzing several years of patient census and medication-use data and using information from proprietary databases (Thomson Reuters) to calculate a "service-specific pharmacy intensity score" for each hospital service, the task force identified five staff-allocation metrics best suited to the medical center's service-based pharmacy coverage model. By applying the methodology, it was determined that CPS expertise was most needed in the UNC Hospitals adult medicine oncology service, the bone marrow transplant service, and the medical and neonatal intensive care units. The tool was initially used to validate the pharmacy department's existing human resource allocation and has since been used to guide budgeting for and deployment of newly added CPS positions. CONCLUSION: A novel tool to guide the application of pharmacy human resources incorporates the objective criteria of patient census, patient acuity, teaching involvement, drug expenditures, and use of high-risk medications. The tool can be used to determine the appropriate allocation and placement of clinical pharmacist resources in a service-based coverage model.

The role of mannitol as a nephroprotectant in patients receiving cisplatin therapy.

OBJECTIVE: To review the efficacy and safety of concomitant mannitol administration with cisplatin therapy to reduce the incidence of nephrotoxicity. DATA SOURCES: A literature search was performed via MEDLINE, PubMed, and the Cochrane Library (1945-August 2011) using the terms mannitol, cisplatin, nephrotoxicity, and forced diuresis. Reference citations from the publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: The search was limited to studies conducted in humans. All studies in which mannitol was used for forced diuresis with cisplatin therapy were evaluated. DATA SYNTHESIS: Cisplatin therapy can lead to transient and permanent renal impairment. Molecular and histologic changes occur in the renal tubules, which contribute to nephrotoxicity. The adverse effect profile of cisplatin is well documented, but the prevention strategies to alleviate renal impairment due to treatment are less understood. Mannitol plus hydration has been used for several years to alleviate toxicity associated with cisplatin therapy. However, the data for mannitol administration have not been convincing. When the use of mannitol and hydration is compared directly to hydration alone, mannitol shows no benefit. In some patients, not only was mannitol not protective, its administration was associated with worsening renal function. CONCLUSIONS: Although mannitol plus hydration is used to decrease cisplatin-induced nephrotoxicity, there are no compelling data that the addition of mannitol is more nephroprotective than the use of hydration alone. Appropriate hydration remains the most reasonable strategy to reduce the incidence of cisplatin-induced nephrotoxicity.

Kinetic and mechanistic insight into the thermodynamic degradation of saxagliptin.

The dipeptidyl peptidase-IV inhibitor saxagliptin (Onglyza) can undergo a thermodynamically favored cyclization to form the corresponding cyclic amidine. The kinetics and mechanism of this conversion were examined to develop a commercial synthesis that afforded saxagliptin with only trace levels of this key byproduct. Important findings of this work are the identification of a profound solvent effect and the determination of an autocatalytic pathway. Both of these phenomena result from transition structures involving proton transfer.

Vemurafenib (PLX4032): an orally available inhibitor of mutated BRAF for the treatment of metastatic melanoma.

OBJECTIVE: To summarize the preclinical and clinical data on vemurafenib, approved by the Food and Drug Administration (FDA) on August 17, 2011, and discuss the drug's clinical advantages and limitations. DATA SOURCES: An English-language literature search of MEDLINE/PubMed (1966-August 2011), using the terms PLX4032, RG7204, RO5185426, vemurafenib, and metastatic melanoma, was conducted. In addition, information and data were obtained from meeting abstracts, clinical trial registries, and news releases from the FDA. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles and abstracts on vemurafenib were included. Clinical trial registries and meeting abstracts were used to obtain information regarding ongoing trials. All peer-reviewed articles containing information regarding the clinical safety and efficacy of vemurafenib were evaluated for inclusion. DATA SYNTHESIS: Before the recent approval (March 2011) of ipilimumab, there was no first-line standard-of-care therapy, with proven overall survival benefit, for the treatment of malignant metastatic melanoma. Unlike ipilimumab, which acts through immune-modulation, vemurafenib is a novel, molecularly targeted therapeutic with preferential efficacy toward a specific mutated oncogenic BRAF-signaling mediator. In recently published results of a Phase 3 clinical trial comparing dacarbazine with vemurafenib, vemurafenib prolonged progression-free and overall survival, with confirmed objective response rate of 48% (95% CI 42 to 55) versus 5% (95% CI 3 to 9) for patients who received dacarbazine (p < 0.001). CONCLUSIONS: Vemurafenib offers a novel, first-line, personalized therapy for patients who have mutated BRAF. Clinical trials of vemurafenib in combination with ipilimumab or other targeted or cytotoxic chemotherapeutic agents may provide more effective regimens with long-term clinical benefit.

Integration of a clinical pharmacist into the hematology-oncology clinics at an academic medical center.

PURPOSE: The development, implementation, and early experience with a program providing clinical pharmacist services at the hematology-oncology clinics of a university teaching hospital are described. SUMMARY: With funding from a university research grant and other sources, a pharmacist was hired to launch a new program addressing four goals identified in a needs assessment: (1) improved management of supportive care, (2) enhanced education of patients receiving complicated chemotherapy regimens, (3) improved efficiency in the chemotherapy infusion unit, and (4) development of an experiential learning opportunity for pharmacy students and residents. The pharmacist hired to lead the ongoing program was a state-approved clinical pharmacist practitioner (CPP) who had authority to prescribe with physician oversight under established protocols. EXPERIENCE: An oncology supportive care consultation service implemented by the CPP in collaboration with a nurse and a physician served 89 new patients in its first 18 months of operation; during that period the CPP made 186 interventions and wrote 136 prescriptions. The CPP also established a chemotherapy counseling service that provided more than 900 bill-able patient education sessions over 18 months. In addition, the CPP launched an effort to increase use of a rituximab rapid-infusion protocol among eligible patients. The creation of the new oncology pharmacist position has given dozens of pharmacy students and residents a new opportunity for interaction with oncology clinic patients and other health care team members. CONCLUSION: Integration of the services of a CPP into the hematology-oncology clinics has helped achieve goals set by physician, nursing, and pharmacy leaders.

Pyrazolopyridine Inhibitors of B-Raf(V600E). Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors.

The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.