An Interview with Denny Fleming

This month our interview comes from Vellore in Tamil Nadu, India. Denny Fleming, honorary professor at the Clinical Pharmacology Unit of the Christian Medical College, kindly shared her experiences. Denny completed her academic formation in Birmingham, United Kingdom, and has worked at the National Health Service (NHS), the University of Science and Technology in Kumasi, Ghana, and clinical trials in osteoarthritis, Roussel Uclaf, UK, prior to joining the Unit in Vellore in 1998.

Denny’s story reflects typical and unique challenges, but also a great deal of achievements, many of which have been supported through collaborations with IATDMCT colleagues.

Can you tell us a little bit about your respective roles? What is a typical day like for you?

I am not sure that a ‘typical day’ exists. I can be sure that any day will involve some departmental administration. As a member of the Ethics Committee of our Institutional Review Board and the Data Safety Monitoring Board of the institution some days will involve looking through submitted proposals or reviewing ongoing studies. What I enjoy as part of the IRB is that periodically I am able to have some input to help young medics and scientists do good research. This is also the side I enjoy when giving lectures to our MD Pharmacology postgraduate students or guiding someone in their thesis. Periodically I don a laboratory coat and sit with one of our technical staff as we develop or validate an assay. Back at my desk a proposal may need work or some time may be grabbed to do some Pmetrics for tacrolimus (with help from Dr J.B Woillard in Limoges). Recently however, for me, there has been a departure from the TDM work. More of my time is being spent on the assays for and issues of newborn screening for amino acid, urea cycle and fatty acid oxidation disorders as well as liaising with different individuals to try form a team in C.M.C for these metabolic issues. All of this is very different from TDM and yet very similar as we want the very best for each individual.

Is there anything that your laboratory does or that is done at your hospital that you would consider innovative in terms of TDM and Clinical Toxicology?

There are a number of stories but I will limit them. Hopefully this will encourage others who are starting a TDM service to persevere and learn as you go.

The first immunosuppressive drug that we started to monitor was mycophenolic acid at the request of a visionary nephrologist Dr George T John. One of our first patients taking Cellcept showed no MPA peak on the chromatogram for 6 hours and we wondered what was happening. There was no restriction on food at that time and a high fat content breakfast was found to be the problem. We next learnt that a ‘light’ breakfast meant a biscuit and cup of tea to some but to others meant 2 glasses of milk instead of 4 with one large portion of rice instead of 2 and so on, you get the picture. This led to the first of the good practices in our TDM service. Since that time for any drug, prior to the day of the test the patient comes to the Unit or contacts the Unit and they are given any special instructions regarding food (very specific), the timing of their medicines (perhaps also in relation to food) and they are also helped to understand the importance of compliance. The patients continue to follow many of these instructions once they return home. We have to bear in mind that India has 22 official languages and so any written instructions must be available in more than one language. Each of our staff speaks from 2 to 5 Indian languages as well as English. This has led over time to very well informed patients.

As a TDM team we have an amazing opportunity at C.M.C as all transplant patients stay in the Vellore area for 6 months post transplant. When we started the MPA AUC monitoring patients had no problem coming and sitting for long periods of time in order to preserve the precious kidney. In fact they would still not object but of course this specimen collection time has been reduced with LSS equations and now hopefully more so as we move to individualized models. However, requiring a patient area for those initial multiple blood collections led to the second of our good practices in our TDM service. Since 2001 every patient, who is able, for any test comes to the Unit. We have seating for up to13 patients and 2 beds. Blood is not taken in some remote location (except a few places and here we have given specific instructions to the staff). In the Unit an appropriately timed specimen collection occurs and all the pertinent details are recorded including demographics, all co-medications, dosages, date of transplant if applicable, height and weight along with any untoward events that have occurred recently such as vomiting or diarrhea (which may influence if the test is performed or postponed) etc.

In talks we try and emphasize that it is not just the concentration that is important but the history behind the concentration.

This tight control of the TDM tests means we do the best for the patients and has resulted in some good translational research.

The last story was due to the very different and variable absorption profile of one of our mycophenolate preparations. It has meant that we run the MPA assay concurrently with specimen collection which allows us to monitor the profile and ensure that all is ok for our calculations prior to the patient leaving the Unit. We hope that modeling will also help this scenario in the future.

When we first started the TDM service for nephrology a number of the then junior faculty (and some senior faculty) did not see much point in ‘this TDM’ and had no problem voicing this opinion. They were in the “We have always done it this way” mode of thinking. A few years ago and with a few very difficult kidneys saved these junior faculty, now senior faculty, bought us a cake to say thank you and in their words “we don’t know what we would do now without ‘this TDM’.”

Is there anything that you’ve seen elsewhere or heard about and thought “I’d like to incorporate that idea at my center”?

My colleague Dr Binu and I had the opportunity recently to visit Cincinnati Children’s Hospital and met with Dr Sander Vinks and Dr Kenneth Setchell, Director, Mass Spectrometry Lab, Professor.  We were able to see the work on paper spray chromatography which was amazing and we look forward to this being available.

What sort of research do you have on the horizon that you think might influence clinical practice in the future?

Last year Dr Michael Neely together with Dr J.B Woillard came to C.M.C to be part of a workshop supported by the travelling lectureship program of IATDMCT. They were also able to help us make progress in our work with Pmetrics. In March of this year Dr Binu Mathew, professor in the Unit spent some time in Dr Neely’s Unit for further training in Pmetrics. Developing models for many of our existing drugs as well as antibiotics and antifungals is a major drive of the faculty. Already, from the work done by Dr Sumith Mathew, Assistant Professor in the Unit, the surgical ICU team have changed their dosing practice for meropenem.

What do you consider is the future for TDM and CT? What are you excited about? What are the challenges we face?

I believe that issues such as real time monitoring, pharmacogenomics driven initial doses of drugs and pharmacometrics are going to become far more common place. These are exciting developments but equally exciting to me are aspects of our work which will never be big international news. As a hospital we are linked to 180 plus small mission hospitals in the rural areas of India and we are working to bring dried blood spot monitoring, at $4 or less per test, for the inexpensive older anticonvulsant drugs which are the mainstay for these patients requiring antiepileptics. Then I imagine the next stage, with pharmacometrics we give individualized predictions for low income remote patients. This is an exciting future for TDM.

The challenges: There is the challenge of ignorance. One of our faculty visited the laboratory of another large hospital a few months ago. He started to talk about TDM and this was the reply he got, ‘Oh, our doctors are all seniors so they do not need TDM.’ We have to be present in medical forums and educate, then educate and then educate some more. Also in the words of one of our colleagues who taking the Nike logo ‘Just do it’ said, ‘Don’t just do it, do it right.’

I agree wholeheartedly with all that Professor Walson wrote (Compass Sept 2014) and we still face the same problems. People’s perception of TDM/CT definitely has to change from just wanting some “number” to compare to a “normal range”. It is also very true that the whole area of medicine is extremely resistant to change. My husband and I worked in Africa for a time and the system for recording drug administration on the wards had many problems. Everyone knew the problems but nobody wanted the trouble of implementing change. So a couple of us, in consultation with many physicians (which took a year), re-designed and changed the recording sheets but only introduced it onto our wards. After some time the staff from other wards were asking why they did not have this. We gladly gave it to them and in this way it spread through the whole hospital. The challenge for TDM/CT is much bigger than this but one way to tackle the challenge may be to identify visionary senior and junior physicians and work with them in such a way that others want what they have got. Easier said than done, I know.