clinical initiatives, research and current updates in treatment
Getting to the Guts of Cancer Immunotherapy Response Kate Siede, Epic Pharmacy Newcastle Over the past decade, interest in the human microbiome, bacteria, viruses and fungi found in and on the human body, has increased considerably.1 A significant driver has been the realisation that the microorganisms that populate the microbiome are not simply passengers in the host. Technological advances have facilitated large-scale analysis of the genetic and metabolic profile specifically of the gut microbiome.1 Through these insights, the gut microbiome can be thought to direct immune system function and can either promote health or initiate chronic disease.1,2,3 Both animal and human studies have also investigated how the gut microbiome can influence response to different classes of medications.4,5,6,7,8,9 This article will focus primarily on the influence of the gut microbiome composition on checkpoint inhibitor immunotherapy, drugs that activate the immune system to attack tumours e.g. ipilimumab, nivolumab and pembrolizumab. Preclinical studies have examined the relationship between gut microbiome composition and T cell response to checkpoint inhibitor therapies in mice with melanoma.5,10 Two studies have demonstrated that the anti-tumour effect of these agents was influenced by the microbiome composition; in these cases efficacy was particularly dependent on bacterial species B. fragilis and Bifidobacterium.5, 10 In each of these preclinical mice models, transfer of the “responder” microbiome profile to “non-responder” mice through faecal transplant elicited improved tumour control, suggesting that the gut microbiome modulates tumour response.5,10
Two new clinical studies have further explored the relationship between the gut microbiome and immunotherapy response in humans being treated for melanoma and epithelial tumours.6,8 The results are in line with previous animal models and further demonstrate that composition of gut bacteria can influence response to immunotherapy. Firstly, the oral and gut microbiomes were examined in patients undergoing checkpoint inhibitor immunotherapy to treat melanoma.6 Significant differences were observed in the diversity and composition of the patient gut microbiome in treatment responders versus non-responders. Patients with high Faecalibacterium abundance, meaning a greater diversity in their gut bacteria, had a significantly prolonged progression free survival (PFS) versus those with less diversity. However, patients with a high abundance of Bacteroidales had a shortened PFS compared to those patients with less Bacteroidales.6 Analysis of the patients’ immune responses revealed that those with the beneficial microbes tended to have more immune cells, which may be more likely to infiltrate and kill tumours. Transplanting the microbes from responding patients into germ-free mice and monitoring their response to immunotherapy treatment yielded similar positive results as was observed in humans.6 Another study explored the possibility that dysbiosis, or an imbalance in the microbiome associated with either malignant disease or due to concomitant antibiotic (ATB) use, could contribute to immunotherapy resistance in both tumour-bearing mice and cancer patients.
It was identified that mice treated for 14 days with a broad spectrum ATB had significantly compromised anti-tumour effects and decreased survival when treated with checkpoint inhibitor immunotherapy. ATB use was then examined in human patients with advanced non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) or urothelial carcinoma being treated with check point inhibitor immunotherapy. Out of a total of 249 patients, 69 (28%) received antibiotics ( -lactams, fluoroquinolones or macrolides) within two months before or one month after the first administration of immunotherapy. ATBs were generally taken for common indications, such as dental, urinary and pulmonary infections. Both median PFS and overall survival (OS) were significantly shorter in the ATB-treated group compared to the non-ATB-treated group, with a median PFS of 3.5 months versus 4.1 months, respectively, and a median OS of 11.5 months versus 20.6 months, respectively.8 These studies show that the composition of gut microbiome significantly influences the response to immunotherapy in both human and animal models. Of note is the trend of improved response rates to immunotherapy where gut microbiomes were more diverse suggesting that potential therapeutic modulation of the gut microbiome may be of benefit to patients about to initiate treatment. Lifestyle factors such as judicious use of antibiotics, introduction of high fibre diets containing pre and probiotics and exercise may be ways of improving patients underlying gut health to assist in potentially enhancing checkpoint inhibitor immunotherapy response. References are available on request.
Drug Dosing in Obesity Larissa Whitely, Epic Pharmacy Wesley
In Australia approximately 65% of adults are either overweight or obese of which 30% are obese.1 An increasing prevalence of obesity has highlighted a lack of evidence relating to the accurate dosing of obese patients.1 There are only a few trials available that have studied the effect of increased body weight on the way in which drugs are processed by the body.1 Generally, dosing in obese patients is often extrapolated from clinical studies in which obese patients are underrepresented.1 Consequently, the current recommendations for the dosing of medications in obese patients is ambiguous.
Certain comorbidities such as type 2 diabetes mellitus (T2DM) may be overlooked, as they are generally considered as ‘adult diseases’.4 However, T2DM is now regularly seen in obese children and adolescents.4 Furthermore, T2DM diagnosed in childhood or adolescence is associated with a more rapid progression to diabetes-related complications and a significant proportion of patients have kidney dysfunction.4 Therefore, the renal function of obese paediatric patients with T2DM should be assessed and the drug dosage altered accordingly.
In cases where a drug dosage varies (i.e. weight-based dosing) it is usually calculated based on the patient’s total body weight (TBW). However, this is often inappropriate in obese patients as the increase in lean body weight (LBW) is disproportionate to the increase in adipose (fatty) tissue.1 Patients within a normal weight range have an approximate 4:1 ratio of LBW to adipose body weight.1 In obese patients, this ratio changes to approximately 3:2 (see Figure 1).1 As the majority of cardiac output is directed to vessel rich or lean body tissue, dosing based on TBW may lead to an overdose in obese patients.2 Therefore, LBW may be a more accurate dosing metric than TBW in morbidly obese patients.2
Obesity can also alter the distribution of drugs within the body depending on the drug’s lipophilicity.1 Lipophilicity refers to the ability of a drug to distribute into fatty substances, whereas hydrophilic (“waterloving”) drugs have an affinity for water and stay within the bloodstream. Highly lipophilic drugs such as phenytoin, propofol and midazolam distribute extensively into fatty tissue and so dosing based on TBW may be appropriate.1 However, the risk of toxicity associated with the administration of large doses calculated using TBW must also be considered in conjunction with the drug’s therapeutic window.2 Consequently, dosing based on LBW may be more appropriate for drugs such as propofol where the risks associated with overdose are high.2 Conversely, hydrophilic drugs such as lithium, aciclovir, aminoglycosides, beta-lactams (e.g. penicillins, cephalosporins, meropenem) and glycopeptide antibiotics (e.g. vancomycin) usually remain in extracellular fluid (not distributed into fatty tissue), and therefore it would be appropriate to use LBW for dosing.1
Renal and Hepatic Function
An example that highlights the issue of ambiguous dosing in obese patients is the use of enoxaparin (Clexane®), a hydrophilic anticoagulant, in the treatment of venous thromboembolism.1 The dosing of enoxaparin is usually calculated based on TBW. This results in high doses in obese patients, which may increase the risk of significant adverse effects (e.g. bleeding) and thus the dose is often ‘capped’ in clinical practice.1 However, this can lead to sub-therapeutic drug levels particularly in morbidly obese patients, as drug clearance increases with body size.1 Consequently, a dose based on LBW rather than TBW may be warranted.
Due to the increasing prevalence of obesity, health professionals need to be aware of the issues relating to the dosing of drugs. Altered proportions of fatty versus lean body tissue results in large variances in how drugs are processed by the body and therefore changes to dosing calculations need to be considered. Furthermore, comorbidities that affect drug metabolism or clearance must also be taken into consideration. However, there is little evidence to guide dosing in obesity, and even less so in children. Consequently, more research is required to assess the relevance of other dosing parameters, such as LBW in obese patients.
The issue of dose calculation is further complicated in obese paediatric patients where evidence is scarcer and co‑morbidities associated with obesity must be taken into account.3
References are available on request.
Figure 1: A comparison of the proportions of lean and adipose body weight in a normal weight patient versus an obese patient.1
Total body weight
80% Normal weight
Total body weight
Not only should renal function be analysed, but also hepatic function. Obesity is associated with a spectrum of liver abnormalities collectively known as non-alcoholic fatty liver disease (NAFLD).5 NAFLD is the most common cause of liver disease in children, with its prevalence estimated at about 38% in obese children.5 Altered hepatic function affects the metabolism of numerous medications. Paracetamol is one such drug that is commonly used in paediatric patients. The presence of NAFLD may place patients at an increased risk of toxicity.5 This is further compounded in obese paediatric patients where drug doses are traditionally calculated using TBW (i.e. mg/ kg).3 Paracetamol is a hydrophilic drug and its dosing is recommended to be based on ideal body weight in obese children, as the use of TBW can result in high concentrations and may lead to overdose and toxicity.3 Additionally, care must be taken not to exceed the maximum adult dose in obese paediatric patients where TBW is used to calculate doses.3
Research from our staff
In 2017 our pharmacy staff conducted a number of research projects. Of these, 5 were presented in various forms at the annual Society of Hospital Pharmacists (SHPA) and the Clinical Oncology Society of Australia (COSA) conferences. We don’t often share this work so we have included 2 of these projects (2 more will follow in the next edition) to give you some understating of our innovations.
Clinical and General Pharmacy Mandatory Training Program and an E-Learning Platform Stacy La Hood, Russell Hill and Chris Giles – Icon Group Pharmacy Practice Unit
Aim To determine whether the E-Learning platform meets business requirements and improves the culture around medication safety.
Method The Icon Group Pharmacy Practice Unit is a clinical governance team responsible for developing a framework for continual improvement that ensures high standards of service in both clinical and general pharmacy practice. In March 2015, the Unit introduced mandatory training to all Epic Pharmacy pharmacists and technicians, delivered through an on-line learning platform, Learning Seat. A three phase roll out was planned, including a mix of in-house content training and assessments, and external online training (e.g. National Prescribing Service (NPS) Moodles), for which certificates of completion were required to be uploaded into the system. A survey of perceptions of benefit, and content relevance was sent electronically to 245 staff. An analysis of training completion rates by pharmacy was undertaken.
Results Survey respondents by role
Over the 15 month period, 1339 assessments had been assigned. The overall completion rate of assessments was 72%, with individual sites ranging from 47% - 92%.
Overall completion rates of assigned assessments 100%
User perceptions (as an average) Most useful/ significant 5
Overall survey completion rate was 33% (80 respondents), with pharmacists and technicians at 34% and 31% respectively.
Ease of use of online platform
Benefit to individual’s practice
Benefit to team’s practice
Least useful/ significant
82% of participants thought that mandatory clinical training had a positive effect on organisational culture around medication safety.
Which assessments have you found worthwhile (as a %)? 70% 60%
Results showed completion rates varied considerably between sites.
The Icon Group Pharmacy division consists of three different pharmacy brands - Epic, Icon and Slade. The mandatory program had been introduced to Epic pharmacy staff at the time of this project.
NPS Moodle – Medication Safety
Understanding the Medicine Management Pathway
Dispensing Chemo Best Practice Handling, Supply, Storing & Repacking
Intrathecal NPS Moodle – Chemotherapy NIMC
When asked if current and future assessments were worthwhile, 78% responded “yes”. Relevance of content received a positive response of between 51% - 94%.
A program should be developed to increase manager’s accountability for staff completion, and improve staff engagement utilising successful strategies from top performing sites. Online training should be made accessible to all Icon Group pharmacy staff. The survey has demonstrated the program is worthwhile however we need to move the program from average to Epic!
The Invisible Pharmacist
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Rachel Taylor – Epic Pharmacy Port Macquarie
Background At a recent hospital accreditation survey, nursing staff were asked how frequently they saw a clinical pharmacist on their ward with nursing staff stating twice a month. Data collected from intervention statistics and electronic consult notes can prove that the clinical pharmacists were on the ward at least once every day. Research and a survey were conducted to try to explain the lack of visibility of clinical pharmacy staff.
Aim To provide a nursing staff perspective on the aspects of pharmacy services that were of most impact and visibility to them.
Methods A survey was presented to randomly selected nursing staff on nine different wards. Data of clinical pharmacy activities were collected on the same day as the survey to show the perceived ward presence of clinical pharmacists versus actual presence. International literature was reviewed on the perception of clinical pharmacy service provision.
6had/9 a clinical wards had
pharmacist visit that day
with the reason being logged on an intervention or on an electronic consult note
surveys were returned
noted that clinical services had been supplied to the wards that day
could not name one member
of the pharmacy team
of those surveyed
of the pharmacy team
could only name one member (14 names were possible)
Conclusion The pharmacy clinical services did not appear to be visible to the nursing staff in over 80% of those surveyed. Services such as imprest management and dispensing (ie roles related to drug supply) were much more visible as a service provided by pharmacy. The personality type of the hospital pharmacist is perhaps one of the reasons for their lack of visibility, and this aspect requires further research.
If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: firstname.lastname@example.org Every effort has been made to ensure this newsletter is free from error or omission.
In this issue: Getting to the Guts of Cancer Immunotherapy Response, Drug Dosing in Obesity, Epic Research Articles.