Pharmacokinetically Guided Dosing: The Way Forward?

David J. Kerr, CBE, MD, DSc


December 15, 2022

This transcript has been edited for clarity.

I'm David Kerr, Professor of Cancer Medicine at the University of Oxford.

You probably don't know this, but when I was training in Glasgow, I trained in clinical pharmacology as well as medical oncology, which is my chosen medical specialty. In those days, all we had really were cytotoxic drugs. It was unusual at that stage for people to apply, let's call it conventional clinical pharmacologic principles, to the delivery of chemotherapy.

We had a fantastic group, the Pharmacology Metabolism Group. Some of the giants of European oncologic pharmacology were members. We had a great time in those early days trying to link the pharmacokinetics and the pharmacology of drugs to their side effects and efficacy profiles.

There's a recent, very nice study by a caucus of Dutch groups in which they looked at using pharmacokinetic principles to improve the delivery of oral targeted drugs, predominantly tyrosine kinase inhibitors. They claim that there's some correlation between exposure and efficacy. It's a large, multicenter study and they enrolled about 600 patients, almost 500 of whom were eligible for the particular study that they followed.

They used sophisticated population pharmacokinetic models that we won't discuss in detail at all, you'll be relieved to hear. They are taking blood samples serially from patients over the period of some weeks and months. They could adjust the dose of the drug to get it into what the literature suggested was the right range.

When we think about pharmacokinetic modeling, we think about two important dose levels. There's the minimum acceptable threshold for activity, and above that, there's a threshold for toxicity. Between that, there's something that we call the therapeutic window. We like to try to adjust the drug dose so it is within this window, avoiding excess toxicity up here and avoiding underdosing down here. Forgive my wiggly fingers, but that's the basis of it.

It's a nice study. It was an ambitious one, with 24 different drugs across a whole range of different tumor types. It's impossible, really, to make any observations of correlation between pharmacokinetics and outcome, such as progression-free survival and so on. That just wasn't in the cards at all.

They did show that a significant proportion of patients were underdosed. Their plasma concentrations were below our minimum acceptable concentration. By using this model in a multicenter setting in many Dutch hospitals, they demonstrated the practical possibility and the feasibility of using a pharmacokinetically guided approach to adjust drug levels to push them up within the therapeutic window.

As I said, because of the nature of the study — the number of drugs, number of tumor types — it was impossible to correlate with outcome in any way that made sense, but it did show that it was practically possible. It showed that a significant proportion of patients, almost 50%, had drug levels that were considered to be too low in at least one of their readings.

What else did we learn? We talk about interindividual variation. That's the difference between you and me. We metabolize drugs in a different way.

Intrapatient variation seems to be really important in this as well, because they found that by following patients serially, sometimes they were within the therapeutic window, but then in second or third readings, they were outside of it. There is an intra-individual variation, and that may depend on the time of day of taking the drug, was it taken with food, were there any concomitant medications, were there any other physiologic events going on? There is a whole host of other factors that, again, add to the complexity of the model.

I would love to be able to demonstrate with clarity a clear concentration-effect relationship between measuring drug concentrations in the bloodstream and outcome, and adjusting those in an individualized way. It's personalized medicine. We've talked about this before. When you think about what we, as doctors, control, it's drug dose delivery. We can't control the patient's genetics or their somatic germinal mutational landscape, but we can respond to it.

We can control drug dose. If only we could do it in a cleverer way, perhaps using pharmacokinetic guidance, then that would be an optimal means of personalizing drug therapy. This Dutch study has demonstrated that it's practical; that it's feasible; and that what we now need are much larger, well-constructed studies looking at outcome.

The purists would say that we should have randomized studies of conventional dose vs pharmacokinetically guided dose. I sort of agree with that, to be honest with you. If we really wanted to have a go, if it's worth the hassle of looking at these pharmacokinetic tests, I'd like to be able to demonstrate that outcomes would be superior, that treatment would be safer, and people would live longer and live better. That's a challenge that I make to our pharmacokinetics community out there.

Have a look at the paper and see what you think of it. I think it's a step forward. It's reawakened in me that old flame from when I was a kid all those years ago about wanting to do these sorts of experiments.

Thanks for listening, as always, and for the time being, over and out. Thank you.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

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