This month we have a real treat: we hear from Jan-Willem Alffenaar, currently Chair of Clinical Pharmacy between the University of Sydney and Westmead Hospital, Sydney, Australia. Jan-Willem has had an amazing career that spans the globe, starting in the Netherlands and currently in the exact opposite corner of the world. This was a really fun interview as we caught up by video conference (photo). He talked about some of the numerous innovative approaches to TDM that he’s been involved in, most recently micro volume saliva testing with a mobile UV-spectrophotometer. We also discussed some really novel ideas he’s been thinking about, like combining Fitbits with TDM (the guy’s an ideas-factory!) Thanks for sharing, JWA, and I hope those ideas keep coming!
I have two roles. I’m appointed at the University of Sydney Faculty of Medicine and at Westmeath Hospital, which is part of Western Sydney Local Health District. This is a joint position, and my main role, of course, is in research and education.
Within the School of Pharmacy, I fulfil a role as coordinator of clinical placements, and there is a particular interest of getting more students into the hospital. As a clinical chair at the hospital, I’m in a position to create more research projects or opportunities for clinical placements.
With the Health District, my role is likewise education and research, but focused on hospital pharmacists to advance their skills and provide more training in research, as well as facilitating collaborative research with other medical specialties. I also serve on a number of committees including the Human Ethics Research Committee, Scientific Advisory Committee and Drug Committee.
On a typical day I have a lot of progress meetings with PhD students and pharmacy students to talk about their work, papers, data analysis and other issues. I’ve tried to develop a nice, attractive program for the students so they can meet with several pharmacists, but also have projects on which they can collaborate in multidisciplinary teams. These could be small projects that might lead to new research projects, or existing research projects where they can contribute (such as data collection). I also accompany students on clinical rounds, for example, we went on the AMS ward rounds last week. It’s nice for me to have a little bit of experience again in the hospital, because otherwise I don’t have time to go on those!
I did a lot of work in the past on dry blood spot sampling, but that’s currently not feasible yet at Westmead. I think micro volume saliva testing with a mobile UV-spectrophotometer is really innovative for the field of TDM. We have one device in the lab, and we have developed two essays and are progressing with those. We also have an entry level mass spec. This is very suitable for student projects or for PhDs because it’s just a relatively simple device to use. If you have the latest, most extensive one, you need a highly skilled analytical scientist to operate it and it’s not suitable for working with students. This entry level model permits us to set up a lot of small-scale pilot studies, so you can build a body of evidence to apply for grants and finance larger studies, but also has the benefit of providing students opportunity to work with analytical equipment.
The laboratory at the University Medical Centre Groningen where I used to work has always been at the forefront of implementing technological innovations. Early in my career the triple quad mass spec was introduced in our lab providing amazing opportunities for fast and accurate sample analysis. This enabled short turnaround times allowing real time TDM studies in the ICU for drugs for which no immunoassay was available. Years later, the LCMSMS enabled analysis of dried blood spots, again a game changer for performing studies in remote setting or home sampling. In my opinion, the LCMSMS is therefore the cornerstone for a TDM lab.
I first became interested in TDM of antimicrobial drugs. That simply came from clinical questions from physicians. One of the first questions that came up was whether a half dose of linezolid would be a useful way to avoid or reduce adverse effects. A clinician had read a case study of a patient that had been successfully treated this way. He came and asked, ‘Can we do that here in our hospital as well?’ Sure, we can give half a tablet, but if you give a lower dose, what happens with exposure? Is it still sufficient to kill the bacteria? Do you still have your target attainment? So, we decided to do a proper prospective study in which we gave patients half and normal doses to compare AUCs and see what happened. That’s what I really like: to address those clinical questions by a proper, pragmatic, prospective study design.
Later on, I had a similar question from the ICU in the hospital. At that time voriconazole was just entering the market. It had a loading dose and we already knew that there was quite a bit of variability in drug concentrations. So, we thought ‘What if the loading dose in ICU patients is not enough?’ Because of studies like the one we did and by others, together with instrumental innovations, monitoring of voriconazole is routine in most clinical settings. So, I think the clinical questions make it worthwhile to do the research.
There was a small grant round in our local health district, and I noted a grant application where they used a Fitbit to monitor patient activity, and this was related to how well they were being treated for their mental health condition, with an anti-psychotic or an anti-depressant drug. They looked at whether they could monitor if a patient was doing well using data from the Fitbit, and I thought, this is really fun: it could really add something to the field.
So, I think it’s sometimes just about thinking outside the box and making use of something in your field of practice. There’s so much out there, and I think often we are too narrow minded and are only focused on what is going on in our field of practice.
Another example of thinking outside the box is that we have set up several assays using a mobile microvolume UV/visible light spectrophotometer for drug measurement in saliva. This device is of course traditionally used to measure DNA quantity but could represent an economical way to perform TDM in resource limited settings.
We have a number of projects based on saliva testing and its potential for monitoring in community pharmacy. There is a potential future for such a cheap device in community pharmacy to provide a service similar to blood pressure testing that is currently available, cholesterol testing and similar. We are foreseeing a future scenario where a patient goes to the pharmacy to fill their script and also hands in a saliva sample to monitor drug concentrations for their chronic medications. We can see whether their levels are still stable, or affected by a drug-drug interaction, or their condition has changed, or they’ve lost a significant amount of weight because they’ve started to exercise, and so on. So, there are a lot of opportunities for easy access monitoring in the community.
I think the future lies with detection of patients that can actually benefit from therapeutic drug monitoring. So, we should define which patient benefit, and, of course, we have to do this through clinical studies, data analysis and so on. We cannot say TDM should be done in all patients because then there’s clearly a problem with standard dosing. My feeling is that this approximately fits the 80:20 rule, so 20 % should receive TDM while 80% should be fine without it. The key will be in finding patients who will benefit, patient not responding to treatment, patients at risk, patients with adverse effects, etc.
And if we’re going to do TDM, we should do it properly, so we need to select the most predictive time points for sampling. If a trough is not OK, you should use abbreviated AUCs or something else, and, of course, that can be a burden on the patient if they have to come into pathology and sit there for half a day for sample collection. In those cases, you have to facilitate that procedure by sampling saliva or something else like home sampling with dried blood spot. Then, you should make use of dosing software to make your decisions as accurate as possible. We can involve various technologies to support making these decisions. We can actually do all of this already right now, but it’s not frequently performed fully yet because of all the hurdles. In our work we propose to make the pharmacist a lead in this complex procedure to make sure that it all flows and to ensure continuation of practice.
Regarding challenges in TDM, I think a major hurdle is the financial aspects of it. We need proper reimbursement for all the related activities, especially if we envision a future where we would like to see it being used in community pharmacy and primary practice. For example, it could be as part of the medication review process, discussing therapeutic drug monitoring with patients and performing regular monitoring, using whatever works in the community. A fee for the service could be incorporated in the costing schemes for medication review. That would definitely facilitate implementation in the community for chronic conditions, but also applies for the hospital setting. Currently instruments are distributed across hospitals in a service and you need to send samples, which, of course, is prohibitive for situations where a fast turn-around time is required. In Australia, due to distances, turnaround time can be upwards of a week. There will need to be a change in practice to make it feasible, and reimbursement for the service is a part of that.
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