Projected environmental and public health benefits of extended-interval dosing: an analysis of pembrolizumab use in a US national health system.

BACKGROUND: Health care is a major source of greenhouse gas emissions, leading to climate change and public health harms. Changes are needed to improve the environmental sustainability of health-care practices, but such changes should not sacrifice patient outcomes or financial sustainability. Alternative dosing strategies that reduce the frequency with which specialty drugs are administered, without sacrificing patient outcomes, are an attractive possibility for improving environmental sustainability. We sought to inform environmentally sustainable cancer care by estimating and comparing the environmental and financial effects of alternative, clinically equivalent strategies for pembrolizumab administration. METHODS: We conducted a retrospective analysis using a cohort of patients from the Veterans Health Administration (VHA) in the USA who received one or more pembrolizumab doses between May 1, 2020, and Sept 30, 2022. Using baseline, real-world administration of pembrolizumab, we generated simulated pembrolizumab use data under three near-equivalent counterfactual pembrolizumab administration strategies defined by combinations of weight-based dosing, pharmacy-level vial sharing and dose rounding, and extended-interval dosing (ie, every 6 weeks). For each counterfactual dosing strategy, we estimated greenhouse gas emissions related to pembrolizumab use across the VHA cohort using a deterministic environmental impact model that estimated greenhouse gas emissions due to patient travel, drug manufacture, and medical waste as the primary outcome measure. FINDINGS: We identified 7813 veterans who received at least one dose of pembrolizumab-containing therapy in the VHA during the study period. 59 140 pembrolizumab administrations occurred in the study period, of which 46 255 (78·2%) were dosed at 200 mg every 3 weeks, 12 885 (21·8%) at 400 mg every 6 weeks, and 14 955 (25·3%) were coadministered with infusional chemotherapies. Adoption of weight-based, extended-interval pembrolizumab dosing (4 mg/kg every 6 weeks) and pharmacy-level stewardship strategies (ie, dose rounding and vial sharing) for all pembrolizumab infusions would have resulted in 24·7% fewer administration events than baseline dosing (44 533 events vs 59 140 events) and an estimated 200 metric tons less CO2 emitted per year as a result of pembrolizumab use within the VHA (650 tons vs 850 tons of CO2, a relative reduction of 24%), largely due to reductions in distance travelled by patients to receive treatment. Similar results were observed when weight-based and extended-interval dosing were applied only to pembrolizumab monotherapy and pembrolizumab in combination with oral therapies. INTERPRETATION: Alternative pembrolizumab administration strategies might have environmental advantages over the current dosing and compounding paradigms. Specialty medication dosing can be optimised for health-care spending and environmental sustainability without sacrificing clinical outcomes. FUNDING: None.

Adopting Weight-Based Dosing With Pharmacy-Level Stewardship Strategies Could Reduce Cancer Drug Spending By Millions.

Immune checkpoint inhibitors, a class of drugs used in approximately forty unique cancer indications, are a sizable component of the economic burden of cancer care in the US. Instead of personalized weight-based dosing, immune checkpoint inhibitors are most commonly administered at "one-size-fits-all" flat doses that are higher than necessary for the vast majority of patients. We hypothesized that personalized weight-based dosing along with common stewardship efforts at the pharmacy level, such as dose rounding and vial sharing, would lead to reductions in immune checkpoint inhibitor use and lower spending. Using data from the Veterans Health Administration (VHA) and Medicare drug prices, we estimated reductions in immune checkpoint inhibitor use and spending that would be associated with pharmacy-level stewardship strategies, in a case-control simulation study of individual patient-level immune checkpoint inhibitor administration events. We identified baseline annual VHA spending for these drugs of approximately $537 million. Combining weight-based dosing, dose rounding, and pharmacy-level vial sharing would generate expected annual VHA health system savings of $74 million (13.7 percent). We conclude that adoption of pharmacologically justified immune checkpoint inhibitor stewardship measures would generate sizable reductions in spending for these drugs. Combining these operational innovations with value-based drug price negotiation enabled by recent policy changes may improve the long-term financial viability of cancer care in the US.

Real world use of FLT3 inhibitors for treatment of FLT3+ acute myeloid leukemia (AML): A single center, propensity-score matched, retrospective cohort study.

BACKGROUND: Patients diagnosed with acute myeloid leukemia with a FLT3 mutation (FLT3+ AML) have historically had poor outcomes. While the addition of the FLT3 inhibitors to induction therapy has been shown to improve survival outcomes in FLT3+ AML, interactions and overlapping toxicities between FLT3 inhibitors and standard of care medications used during induction therapy (e.g. azole antifungals, anthracyclines) and logistical barriers have complicated their use. To avoid these concerns, our institution has opted to defer initiation of midostaurin until after completion of induction therapy. However, to our knowledge no study confirming the effectiveness of this strategy for real world FLT3 inhibitor use has been published. METHODS: We performed a single center, propensity-score matched, retrospective cohort study characterizing efficacy and safety of our strategy for use of FLT3 inhibitors in the treatment of FLT3+ AML. The primary outcome was median event-free survival (EFS), while secondary endpoints included median overall survival (OS), overall response rate (ORR), 30-day mortality, duration of neutropenia, duration of thrombocytopenia, consolidation cycle delays, documented infections, and all-cause hospital readmission. RESULTS: A total of 83 FLT3+ AML patients treated with intensive induction therapy were included in the study, of whom 48 were propensity-score matched and analyzed. Baseline characteristics were similar between the patients who received a FLT3 inhibitor after induction therapy and the historical control arm. Median EFS was not significantly different but compared favorably between the FLT3 inhibitor cohort and historical controls (not reached vs 8 months, p = 0.343) with 18-month EFS of 54% and 43% for the two cohorts, respectively. Similarly, no significant differences were noted with regard to median OS (not reached vs 28.7 months, p = 0.752), ORR (79.2% vs 79.2%), or safety outcomes between groups. CONCLUSION: Compared to historical controls, addition of a FLT3 inhibitor to intensive chemotherapy post-induction may improve EFS or OS in a real world patient cohort with longer follow-up and a larger sample size. The omission of midostaurin in induction allowed for the use of an azole antifungal and the intensification of anthracycline dose may have contributed to high remission rates in both groups.

Evaluating the Role of Novel Oncology Agents: Oncology Stewardship in Relapsed/Refractory Diffuse Large B-Cell Lymphoma.

Novel treatment strategies have shifted the treatment landscape for patients with diffuse large B-cell lymphoma, particularly for those with relapsed/refractory disease. However, uncertainty remains regarding the therapeutic value of these novel agents compared to existing salvage chemotherapy regimens. In addition, the high cost associated with these agents puts both patients and health systems at risk of financial toxicity, further complicating their use. The development of clinical pathways incorporating oncology stewardship principles are necessary in order to maximize value-based care. This comprehensive review assesses the efficacy and safety data available for novel treatment options in relapsed/refractory diffuse large B-cell lymphoma and applies stewardship principles to evaluate their optimal place in therapy, with the aim of optimizing safe, effective, and financially responsible patient care.

Insights on developing a field hospital formulary and medication distribution process in preparation for a second surge of COVID-19 cases.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has caused health systems across the country to plan for field hospitals to care for patients outside of traditional healthcare settings in the event of a second surge. Here we describe key considerations for the implementation of pharmacy operations and a field hospital formulary at an offsite location within a 2-week time frame. SUMMARY: Development of an offsite field hospital formulary is first dependent on the location and patient population defined for the field hospital. Creation of a limited formulary for a planned field hospital in Michigan involved reviewing physical space limitations and drug distribution workflows, assessing current prescribing trends, creating drug categories, and creating formulary guidelines to limit formulary options in each therapeutic category. Ultimately, our institution developed a 140-medication field hospital formulary, a process to enable appropriate use of nonformulary drugs, and a mixed operations model including automated dispensing cabinets and a manual cart-fill process. Although the institution did not have to open the field hospital, the process used for developing the formulary and determining distribution models will allow for an immediate implementation if a second surge occurs. CONCLUSION: A methodical approach to developing limited formularies and pharmacy operations in a field hospital setting will allow health systems to establish efficient and effective medication distribution services in the event of a second surge of COVID-19 cases.

Identifying Opportunities for Improvement in Safety and Efficacy of Community Pharmacy Immunization Programs.

OBJECTIVE: To identify opportunities to improve safe and effective immunization delivery in community pharmacies. METHODS: Pharmacy managers from chains in Michigan were interviewed about their company's immunizations programs. A survey regarding immunization training, quality assurance measures, pharmacist comfort level immunizing different patient populations, and resources used in practice was distributed to community pharmacists throughout Michigan. RESULTS: Most pharmacists (88.8%) confirmed they received American Pharmacists Association immunization training and felt they followed the guidelines outlined in that training course very well. No routine reassessment of immunization technique was reported. In a minority of respondents, some issues were identified: (1) not being up-to-date on cardiopulmonary resuscitation certification as required by state law (7.1%), (2) lack of awareness of location of emergency kit (4.2% for epinephrine, 13.5% for diphenhydramine), and (3) feeling uncomfortable immunizing children (51% for children <7 years). CONCLUSION: To address quality control issues identified in the survey, we recommend chain pharmacies incorporate credential checks into annual pharmacy training requirements. Pharmacists may benefit from immunization-related continuing education requirements. State pharmacy organizations may want to take the lead in developing the material to ensure that it is timely and abides by state and federal laws.

Mito-nuclear interactions modify Drosophila exercise performance.

Endurance exercise has received increasing attention as a broadly preventative measure against age-related disease and dysfunction. Improvement of mitochondrial quality by enhancement of mitochondrial turnover is thought to be among the important molecular mechanisms underpinning the benefits of exercise. Interactions between the mitochondrial and nuclear genomes are important components of the genetic basis for variation in longevity, fitness and the incidence of disease. Here, we examine the effects of replacing the mitochondrial genome (mtDNA) of several Drosophila strains with mtDNA from other strains, or from closely related species, on exercise performance. We find that mitochondria from flies selected for longevity increase the performance of flies from a parental strain. We also find evidence that mitochondria from other strains or species alter exercise performance, with examples of both beneficial and deleterious effects. These findings suggest that both the mitochondrial and nuclear genomes, as well as interactions between the two, contribute significantly to exercise capacity.

Human Urinary mRNA as a Biomarker of Cardiovascular Disease.

Background mRNA in urine supernatant (US-mRNA) might encode information about renal and cardiorenal pathophysiology, including hypertension. H, whether the US-mRNA transcriptome reflects that of renal tissues and whether changes in renal physiology are detectable using US-mRNA is unknown. Methods We compared transcriptomes of human urinary extracellular vesicles and human renal cortex. To avoid similarities attributable to ubiquitously expressed genes, we separately analyzed ubiquitously expressed and highly kidney-enriched genes. To determine whether US-mRNA reflects changes in renal gene expression, we assayed cell-depleted urine for transcription factor activity of mineralocorticoid receptors (MR) using probe-based quantitative polymerase chain reaction. The urine was collected from prehypertensive individuals (n=18) after 4 days on low-sodium diet to stimulate MR activity and again after suppression of MR activity via sodium infusion. Results In comparing this US-mRNA and human kidney cortex, expression of 55 highly kidney-enriched genes correlated strongly (rs=0.82) while 8457 ubiquitously expressed genes correlated moderately (rs=0.63). Standard renin-angiotensin-aldosterone system phenotyping confirmed the expected response to sodium loading. Cycle threshold values for MR-regulated targets ( SCNN1A, SCNN1G, TSC22D3) changed after sodium loading, and MR-regulated targets ( SCNN1A, SCNN1G, SGK1, and TSC22D3) correlated significantly with serum aldosterone and inversely with urinary sodium excretion. Conclusions RNA-sequencing of urinary extracellular vesicles shows concordance with human kidney. Perturbation in human endocrine signaling (MR activation) was accompanied by changes in mRNA in urine supernatant. Our findings could be useful for individualizing pharmacological therapy in patients with disorders of mineralocorticoid signaling, such as resistant hypertension. More generally, these insights could be used to noninvasively identify putative biomarkers of disordered renal and cardiorenal physiology.

Endurance exercise and selective breeding for longevity extend Drosophila healthspan by overlapping mechanisms.

Endurance exercise has emerged as a powerful intervention that promotes healthy aging by maintaining the functional capacity of critical organ systems. In addition, long-term exercise reduces the incidence of age-related diseases in humans and in model organisms. Despite these evident benefits, the genetic pathways required for exercise interventions to achieve these effects are still relatively poorly understood. Here, we compare gene expression changes during endurance training in Drosophila melanogaster to gene expression changes during selective breeding for longevity. Microarrays indicate that 65% of gene expression changes found in flies selectively bred for longevity are also found in flies subjected to three weeks of exercise training. We find that both selective breeding and endurance training increase endurance, cardiac performance, running speed, flying height, and levels of autophagy in adipose tissue. Both interventions generally upregulate stress defense, folate metabolism, and lipase activity, while downregulating carbohydrate metabolism and odorant receptor expression. Several members of the methuselah-like (mthl) gene family are downregulated by both interventions. Knockdown of mthl-3 was sufficient to provide extension of negative geotaxis behavior, endurance and cardiac stress resistance. These results provide support for endurance exercise as a broadly acting anti-aging intervention and confirm that exercise training acts in part by targeting longevity assurance pathways.

Dietary composition regulates Drosophila mobility and cardiac physiology.

The impact of dietary composition on exercise capacity is a subject of intense study in both humans and model organisms. Interactions between diet and genetics are a crucial component of optimized dietary design. However, the genetic factors governing exercise response are still not well understood. The recent development of invertebrate models for endurance exercise is likely to facilitate study designs examining the conserved interactions between diet, exercise and genetics. As a first step, we used the Drosophila model to describe the effects of varying dietary composition on several physiological indices, including fatigue tolerance and climbing speed, cardiac performance, lipid storage and autophagy. We found that flies of two divergent genetic backgrounds optimize endurance and cardiac performance on relatively balanced low calorie diets. When flies are provided with unbalanced diets, diets higher in sugar than in yeast facilitate greater endurance at the expense of cardiac performance. Importantly, we found that dietary composition has a profound effect on various physiological indices, whereas total caloric intake per se has very little predictive value for performance. We also found that the effects of diet on endurance are completely reversible within 48 h if flies are switched to a different diet.