Combined use of irinotecan with histone deacetylase inhibitor belinostat could cause severe toxicity by inhibiting SN-38 glucuronidation via UGT1A1.

SN-38, the active metabolite of irinotecan, and histone deacetylase inhibitors (HDACis) such as belinostat, vorinostat and panobinostat, have all been shown to be deactivated by glucuronidation via UGTs. Since they all compete for UGTs for deactivation, we aimed to investigate the inhibitory effect of various HDACis on the glucuronidation of SN-38. This inhibitory effect was determined by measuring the formation rate of SN-38 glucuronide after SN-38 incubation with human recombinant UGT1A isoforms (1A1, 1A6, 1A7 and 1A9) and pooled human liver microsomes (HLM, wild type, UGT1A1*1*28 and UGT1A1*28*28 allelic variants), with and without HDACis. The data showed that belinostat at 100 and 200 µmol/L inhibited SN-38 glucuronidation via UGT1A1 in a dose-dependent manner, causing significant decrease in Vmax and CLint (p < 0.05) from 12.60 to 1.95 pmol/min/mg and 21.59 to 4.20 µL/min/mg protein respectively. Similarly, in HLMs, Vmax dropped from 41.13 to 10.54, 24.96 to 3.77 and 6.23 to 3.30 pmol/min/mg, and CLint reduced from 81.25 to 26.11, 29.22 to 6.10 and 5.40 to 1.34 µL/min/mg protein for the respective wild type, heterozygous and homozygous variants. Interestingly, belinostat at 200 µmol/L that is roughly equivalent to the average Cmax, 183 µmol/L of belinostat at a dose of 1,400 mg/m2 given intravenously once per day on days 1 to 5 every 3 weeks, was able to inhibit both heterozygous and homozygous variants to same extents (~64%). This highlights the potential clinical significance, as a large proportion of patients could be at risk of developing severe toxicity if irinotecan is co-administered with belinostat.

Robotic i.v. medication compounding: Recommendations from the international community of APOTECAchemo users.

PURPOSE: The development of recommendations for advancing automated i.v. medication compounding is described. SUMMARY: Managing the shift from manual to robotic compounding of i.v. therapies requires an awareness of how automation affects practice and how to best implement robotics into current practice. An international panel of pharmacy professionals, researchers, and technology leaders with experience in i.v. robotics collaborated during a two-day meeting in August 2014 to define a general set of principles to broaden the understanding of the fundamental elements of robotic compounding worldwide. Participants were divided into four working groups (technology and safety; drugs and products; personnel; and facilities and quality) to analyze specific aspects of robotic compounding practice. The four working groups produced an initial list of 92 statements. This list was condensed to 35 statements by consolidating similar and overlapping statements from the different work groups. Participants were surveyed again to assess agreement with the 35 statements and solicit additional clarification. Respondents expressed full agreement with 25 recommendations. Six statements received one or more "don't know" responses, with all other respondents in agreement. Four statements had a combination of "don't know" and "disagree" responses. A total of 32 comments were recorded in free-text fields, including requests for clarification and suggestions for rewording the statements. CONCLUSION: An international panel of pharmacy professionals, researchers, and technology leaders with experience in i.v. robotics developed a set of 35 recommendations toward a better understanding of the role of automated i.v. compounding in hospital and health-system pharmacies worldwide.

Improving Wait Times for Elective Chemotherapy Through Pre-Preparation: A Quality-Improvement Project at the National University Cancer Institute of Singapore.

PURPOSE: Cancer treatment occurs predominantly in the outpatient setting. Long wait times for chemotherapy lead to increased dissatisfaction, inefficient use of chemotherapy chairs, and compromised safety when delays result in treatment beyond operation hours. For patients who have undergone review with the necessary investigations by their oncologists on a prior day, a long wait time is more frustrating, because the sole purpose of their visit is for chemotherapy (termed elective chemotherapy). PATIENTS AND METHODS: From February 2013 to September 2013, we conducted a clinical practice improvement program project to reduce wait times for elective chemotherapy and identified late submission of prescriptions, long drug preparation time, and pharmacy review of prescriptions as the main causes of delay in our center. We formulated a workflow to pre-prepare selected chemotherapy up to 1 day before appointments. Selection was based on shelf life, cost, recyclability, and need for premedication. Patients were triaged by telephone before their appointment before pre-preparation. Participation was voluntary, with patients required to consent for liability for cost in event of wastage. RESULTS: Average wait time for chemotherapy was significantly improved by 66% from 65.7 (median, 60; range, 5 to 301) to 22.4 minutes (median, 20; range, 0 to 80 minutes; P < .001). There were no wastages during this period, and treatment for elective patients could start as soon as the center opened if their drugs were pre-prepared the day before. CONCLUSION: Pre-preparation of chemotherapy, together with effective phone triaging, is an effective way to reduce chemotherapy wait time.

Clinical impact of drug-drug interaction between aspirin and prednisolone at a cancer center.

BACKGROUND: Adverse gastrointestinal (GI) events are complications in aspirin and prednisolone cotherapy. The prevalence of adverse GI events would be expected to be increased with cotherapy due to the overlapping toxicities of the 2 drugs. However, there is a dearth of literature investigating how often this interaction causes clinically important adverse GI events. OBJECTIVES: This retrospective study aimed to determine the prevalence of adverse GI events associated with the coadministration of aspirin and prednisolone. The use of gastroprotectant agents was also studied. METHODS: The medical records of patients with cancer prescribed aspirin and prednisolone therapy between January 2007 and June 2011 were analyzed. The duration of aspirin-prednisolone overlap, prevalence of adverse GI events, and details on the concurrent use of other medications were evaluated. RESULTS: The study included data from 142 patients (male, 64.8%; mean [SD] age, 67.4 [11.0] years). A total of 78.9% of the patients were on some form of gastroprotectant, the most common class of which was proton pump inhibitors. The prevalence of adverse GI events was 4.2% (6 patients). Four patients had presented with GI symptoms (abdominal pain, diarrhea, dysphagia, and vomiting); 3 patients had signs of GI injury (duodenal ulcers, iron deficiency anemia, and a Mallory-Weiss tear). The Naranjo algorithm classified 5 patients experienced possible adverse drug reactions (ADRs), and 1 as a probable ADR. CONCLUSION: Our study found that the prevalence of adverse GI events was low and managed to establish a weak association between the occurrence of events and the coadministration of aspirin and prednisolone. This finding, together with the concurrent prescription of gastroprotectants, suggests that the clinical impact of the aspirin and prednisolone DDI is minimal.

Targeted therapy at the end of life in advanced cancer patients.

OBJECTIVE: We describe the use of systemic therapy in advanced cancer patients admitted to an acute care hospital, with a focus on targeted therapy. We aim to spotlight the utilization of targeted agents in the last months of life. METHODS: Adult patients (N=252) with advanced solid tumors who died as inpatients in the National University Hospital, Singapore, were included in this retrospective study. Patients' demographic and clinical data were extracted from hospital records. Information on systemic therapy was extracted from the time of diagnosis and all other data limited to the last three months before death. RESULTS: 187 adult patients received palliative systemic therapy from the time of diagnosis, of which 125 (66.8%) received it within three months of death. Of patients receiving only nontargeted systemic treatment (n=106), 60 (56.6%) and 26 (24.5%) received it within three months and one month of death respectively. Comparatively, 81 patients received palliative targeted systemic therapy, of which 65 (80.3%) and 40 (49.4%) had treatment within three months and one month of death respectively (p=0.001 and p<0.001). Targeted therapy was first initiated in the last three months of life in 38 patients. Oral agents targeting epidermal growth factor receptor (lung cancer patients) and vascular endothelial growth factor receptor (non-lung cancer patients) pathways were commonly employed. Lung cancer patients were more likely to have targeted therapy as their last line of systemic therapy: 26/54 lung cancer patients compared with 29/133 non-lung cancer patients (48.1% versus 21.8%, p<0.001). CONCLUSIONS: Targeted therapy is used in more than half of patients who received systemic therapy within three months of death. The degree to which these agents are being utilized near the end of life suggests the need to reexamine the risk/benefit profile of targeted therapy for this population, and the decision-making process around their use.

Prevalence of the coprescription of clinically important interacting drug combinations involving oral anticancer agents in Singapore: a retrospective database study.

BACKGROUND: There has been a recent increase in the availability and use of oral anticancer agents (OAAs). Drug-drug interactions (DDIs) involving OAAs pose a major concern in oncology practice due to these drugs' narrow therapeutic indices and potential for compromised efficacy and fatal adverse events. OBJECTIVE: To assess the prevalence of the coprescription of potentially interacting drug combinations involving OAAs in Singapore. METHODS: A retrospective review of physicians' electronic prescription records between the years 2007 and 2009 was performed in the largest cancer center in Singapore. An overall prevalence rate of potential DDIs and a prevalence rate for each individual DDI pair were calculated. Logistic regression was used to identify risk factors for potential DDIs. RESULTS: Fifty-eight clinically significant DDIs were selected for evaluation from Drug Interaction Facts and Micromedex DrugDex. A total of 39,772 OAA prescriptions prescribed to 8837 patients were reviewed. Potential DDI coprescription was found in 5.4% of the patients on OAAs and in 4.7% of the OAA prescriptions. The drug pair prescribed to the largest number of patients was prednisolone and aspirin. About half (53.3%) of the observed DDIs were found on the same prescription. On multivariate analysis, older patients, males, and those taking prednisolone had a higher risk for potential DDIs. CONCLUSION: Although limited by the data available, the analysis of prescription records found that ∼5% of patients taking OAAs in Singapore were exposed to ≥1 potentially interacting drug combination.

Targeted therapy at the end of life for patients with lung cancer.

The use of chemotherapy at the end of life is increasing. We characterized the use of targeted therapies in relation to the end of life in non-small cell lung cancer (NSCLC) patients who died in our institution. The frequency of systemic anticancer therapy usage at the end of life was consistent with that reported in other recent studies. The use of targeted therapies, especially epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), was strikingly more common than that of conventional chemotherapy. Targeted therapy was frequently initiated within the last 3 months of life. Targeted agents were also used in sequence, in combination, and in investigational protocols. We conclude that targeted agents, in particular EGFR TKIs, are now the drugs of choice in the systemic treatment of NSCLC at the end of life.

Evidence for disease control with erlotinib after gefitinib failure in typical gefitinib-sensitive Asian patients with non-small cell lung cancer.

INTRODUCTION: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are gaining an increasing role in the management of advanced non-small cell lung cancer (NSCLC). There is mounting interest in the benefit of administering a second TKI after failure of the first TKI, especially in Asian patients, in whom they are expected to be more efficacious. METHODS: We did a retrospective analysis of patients receiving both gefitinib and erlotinib in our institution during a 2-year period. Patients were to have received the second TKI after progressive disease on the first TKI. EGFR gene mutation analysis was done on patient tumor samples. RESULTS: Fourteen patients were included in the analysis, all of whom received erlotinib after progression on gefitinib. Chinese race, females, never-smokers, and adenocarcinoma subtype were predominant in their respective categories. Disease control rate was 64.3% (9 of 14) for gefitinib. Disease control rate for erlotinib administered after progression on gefitinib was 35.7% (5 of 14). All patients who achieved disease control with erlotinib after progression on gefitinib were never-smokers with adenocarcinoma subtype, who had prior disease control on gefitinib. Presence of EGFR mutations predicted for disease control with gefitinib, and for disease control with erlotinib after gefitinib failure. CONCLUSION: A significant proportion of typical gefitinib-sensitive Asian NSCLC patients can have disease control with erlotinib after gefitinib failure. The role of subsequent administration of a second EGFR TKI after failure of the first TKI in advanced NSCLC should be further pursued.