On my way to work this morning, I heard a story on NPR about Plan B emergency contraception (Levonorgestrel), and how the efficacy at preventing pregnancy is reduced in women who are overweight or obese. The story reported that levonorgestrel, the active ingredient in Plan B…
starts losing its effectiveness in women weighing as little as 165 pounds and loses it completely in women who weigh more than about 175 pounds.
A later airing of the same segment I heard on my way home stated that this effect was independent of BMI – so a tall woman who is not even overweight might also experience a reduced efficacy. This text doesn’t appear in the linked story, and I haven’t read the primary study the story references – I didn’t have time today.
Because I was busy making a quick PBPK model to illustrate the impact of differences in weight on levonorgestrel pharmacokinetics.
All but approximately three of my readers just got really confused, so here are some key terms and a very fast primer. Pharmacokinetics is the fate of a substance of interest once it is introduced to a living organism. For example, when you take medicine, say a pill that you swallow, how that drug is absorbed through your GI tract, distributed through out your body, metabolized, and eventually eliminated in your pee or various other routes. PBPK models: physiologically based pharmacokinetic models are mathematical descriptions of all the physiology and biochemistry that influence pharmacokinetics. So to make a model, I describe physiological aspects of the body like the volume and composition of organs of interest, and rates of blood flow to those organs. Then I add biochemical details, like how water or fat soluble the substance of interest is, how quickly it is metabolized and in what tissues, how quickly the substance is absorbed or eliminated in various tissues, and so forth. I incorporate all of that information into differential equations (calculus! fun!) that allow me to simulate exposure scenarios I am interested in.
For levonorgestrel, I was interested in what the blood concentration might look like based on changes in body weight (and associated organ volumes, blood flows, etc.). I focused on three scenarios for a 5’4″ tall woman: a normal BMI, overweight BMI, and obese BMI. I used the low end for each (18.5, 25, and 30, yielding body weights of approximately 109 lbs, 147 lbs, and 176 lbs).
I built a model with explicitly described liver and fat tissues, as well as arterial and venous blood, and the rest of the body lumped together into tissues that are slowly perfused (bone, skin, muscle) and rapidly perfused (brain, visceral organs, etc.). I incorporated chemical specific information for levonorgestrel from the wikipedia page (protein binding, bioavailability) and from the literature (rates of metabolism, Kuhnz & Gieschen 1998).
I made a pile of assumptions that, given enough free time, I could vet against the available literature (i.e. actual data). For one, I assumed that in a 5’4″ woman, as weight increased, some tissue volumes increased and others did not – for example, I assumed that the liver size would be similar in a woman with a BMI of 18.5 or 30.0, but that fat, muscle, and blood volumes would be greater in a woman with a BMI of 30 than a BMI of 18.5. I would need to revisit and expand on these assumptions, especially if I get a look at the original study and it DOES say the observed (lack of) effect was independent of height. I also had to estimate rates of absorption, which I did by visually fitting them to data on blood concentrations in the drug pamphlet (you know, that thing that comes with your prescription drugs that is covered in teeny tiny writing that you immediately throw away). I can provide a lot more detail here, but I think I’ve already provided more than all but three of you care about.
SO ANYWAY. I did a couple of simulations to illustrate my point. Did I ever say what my point is? It’s this: I WAS NOT SHOCKED BY THE NEWS STORY. If you give the same amount of a drug to people of different sizes, without accounting for the size difference in the dose given, you will sometimes see a change in efficacy. That is: if you give a 1.5 mg of levonorgestrel to a 109 lb woman, a 147 lb woman, and 176 lb woman, they will have different blood concentrations of the drug. THE DOSE IS NOT WEIGHT ADJUSTED. Thus, if there is a threshold below which the drug ceases to be effective (LIKELY), it is possible that this might be breached, resulting in some effect (or lack thereof), like…. pregnancy, here. Look, some pictures.
First, here is some evidence that the model I whipped up isn’t complete crap. Predicted blood concentrations of levonorgestrel following a 1.5 mg oral exposure. This is where I visually fitted the oral absorption parameters. If I have time, I can find more pharmacokinetic data to better optimize these parameters, but this is sufficient to support my point.
Next, the point: here you can see model predictions of blood concentration of levonorgestrel after a 1.5 mg oral dose in women with three different BMIs (18.5, 25, and 30).
So there is definitely more fiddling I can do to make the model a hell of a lot better – for instance, if I can get my hands on the weight info for the women represented by the data in the first graph, as it is pretty unlikely that they had an average BMI of 18.5 (109 lbs! That was me in 9th grade! Haaaa!). But, my point is that body weight exerts a SIGNIFICANT impact on maximum blood concentration – it is almost 50% higher in the BMI 18.5 woman compared to the BMI 30.0 woman. That’s potentially a big deal, depending on what the therapeutic index is, and what the outcome is.
Now, as I said, I haven’t read the original study, which is kind of a big oversight. I will. I do think that the pharma company that makes this drug should have addressed this issue before the drug made it to market, but you need a large population exposed before some of these effects come to light – human variability is a big deal, and it’s not like you can do clinical trials for a drug like this on zillions of people.
BUT. Think about all the medicine you take. SO MUCH of it never takes weight into consideration – it’s just “for adults, take two pills” or whatever. Kid medicine does – you choose the dose based on which weight range they fall into – but not grown up medicine! For most stuff, it’s ok – the therapeutic index is wide enough that it doesn’t matter. But it ticks me off. Imprecision BUGS THE SHIT OUT OF ME. Dose matters! Look at the graph! Yes, it is impossible (at this point) to account for all of human variability, but that doesn’t mean we shouldn’t at least TRY to account for something as simple as BODY WEIGHT, does it? Maybe my friend Robin can swoop in here and tell me why I shouldn’t care this much. I hope he does. As it stands, I have had way too much coffee and spent way too much of my day on this mess.
Also, I accidentally saw some of the comments on the article on NPR.org, and now I think humanity is a lost cause, someone please get me some cake.