Interview with Michael Neely

Michael Neely

Chief, Division of Infectious Diseases, Children’s Hospital, Los Angeles
Director, Laboratory of Applied Pharmacokinetics and Bioinformatics
Professor of Pediatrics, Keck School of Medicine
University of Southern California

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

I am a paediatric infectious diseases physician, I also have training in clinical pharmacology and pharmacometrics. I am the Chief of Paediatric Infectious Diseases at Children’s Hospital Los Angeles. I have three hats, really, that I wear. When I wear my clinical physician hat, I see hospitalized children to do infectious diseases consultations about six weeks out of the year, one week at a time. I do a half a day of clinic per month, to see outpatients – not as much as some of my colleagues, but I also, then, wear a second hat which is, of course, administrative, where I have considerable amount of responsibility as the Chief of the division. That entails program building, faculty management, all the things you might expect from being a Chief. And then my third hat, which perhaps is the one I enjoy the best, is my research hat. I do a lot of work on PKPD modelling and dose optimization. More recently I am launching a laboratory-based program looking at mycobacterium abscessus, trying to optimize therapy for what is quite an evil little pathogen.

Is there anything that is done at your centre that you would consider innovative?

What we are most well-known for in the modelling world is our use of the non-parametric type statistics, where we assume nothing about the underlying probability distributions for our parameters when we perform Bayesian calculations or model building, for example. So, our dosing algorithm, in turn, is unique. We implement it in a program called BestDose, which we have currently licensed to InsideRx. The algorithm that we use to calculate the ‘best dose’ for a patient is unique. I think that it has been quite extensively clinically validated. We have published several prospective studies, as have other collaborators, such as Anders Asberg in Norway, including randomized prospective studies of BestDose versus local experts. In all of these studies, the algorithm used in BestDose has been shown to be accurate, and have a positive effect on clinical outcomes. I think that is probably the most identifiably unique thing that we do.

What technological innovations have entered into use during your career that have permitted a change, or evolution, in practice?

As far as revolutionary technological advancements, the improvement in the power of personal computers and the creation of the Internet (now I’m dating myself) rank at the top of many. These tools permit the use of models to optimize dosing at the patient’s bedside and facilitate the sharing of information in ways that were not possible twenty years ago or more.

How did you become interested in your area of expertise?

I can remember the exact moment and patient who inspired me to become interested in TDM. When I was a second-year pediatric resident, I cared for a young boy in the pediatric intensive care unit who needed continuous dialysis for renal replacement therapy. He had a serious infection and the infectious disease consultants recommended cefepime. I questioned what the correct dose would be, given his sepsis and renal replacement therapy. Nobody seemed sure, until the head of the ICU, who happened to be a clinical pharmacologist, offered to measure cefepime concentrations in his laboratory. We discovered that the dose he was receiving was completely wrong. After that, I was hooked!

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

Well, I watched at least one, I think two, possibly three presentations by Birgit Koch at the meeting this year and I was green with envy. She has a phenomenal set up where she runs a lab that measures where I think it was over 120 different drug compounds. She has a well-organized therapeutic drug monitoring and dose optimization service. Just incredible. The level of service she provides to not only her hospital, but to the entire country, I think is inspiring. And there are other centres like that too. I have some very good friends from Limoges, France: Pierre Marquet, John Baptiste Woillard, Franck Saint Marcoux. They’re all members of the Association, and they do a very similar thing [to Birgit] in France. Again, I’m just green with envy with what they can do, and the impact that they can have on so many different hospitals, physicians, pharmacist and patients.

So really what you’re wanting are the analytical services, the availability of a rainbow of tests and models?

Not only the analytical services but more people to help interpret those results. It’s always a bit of a struggle in the United States. I was really captured by Pierre Wallemacq’s opening presentation [at the congress] where you looked at the number of TDM samples sent by a nation: the United States was the biggest piece of the pie. But, when you adjusted for population size, suddenly not so much. I do find that it’s sometimes a bit of a struggle in the United States to get our colleagues to except the idea that one-size does not actually fit all. Having said that, I feel there has been movement in the last few years. Precision dosing is catching on, and the FDA hosted its first workshop where I was lucky enough to be a presenter [August, 2019]. In fact, our group was the only group that had two presenters at that workshop. So I do think things are moving in the US, but it is just slow. [Several IATDMCT members presented. Event details, and presentations available here]

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

I am very interested in the use of biomarkers to optimize therapy. Particularly with infectious diseases, traditional outcomes such as resolution of fever or microbiologic sterilization may be delayed or difficult to measure.

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

I don’t know that they’ve changed at all. The benefits I think are clearly that we can impact the lives of individual patients in a positive way. The difficulty, I think, is it’s sometimes very hard to know ahead of time who that patient might be. Certainly one-size-fits-all dosing is not entirely bad. It does serve even perhaps the majority of patients. But the thing is do you want to be, or do you want your patient to be, the one at the whatever size of the tail of that bell-shaped curve is. You don’t know who’s going to be in that. So by optimizing therapy for everyone we enhance the effects, reduce the adverse effects – for at least some of them – and I think that’s always been the benefit of this.

Also, it naturally leads to a more individualized relationship between provider and patient, because there is just more care and attention paid to therapy. The challenge is, again, what we’ve always faced all along: how do we convince the rest of the world? How do we convince our colleagues that this is something that is worthwhile, and cost-effective? How do we design clinical studies that can show that? How do we choose the right end points? How do we consider the statistics carefully, so that we actually likely to generate data and to generate publications that are convincing? Always a challenge.