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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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April 2, 2009

The Polypill Rides Again

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Posted by Derek

There are a lot of recommended mediations for people at cardiovascular risk. ACE inhibitors and diuretics for blood pressure, a bit of aspirin for anti-thrombotic activity, most likely a stain for cholesterol levels. There are plenty of people who are taking all of these at once, and millions are taking some subset of them. So why not combine them into one good-for-what-ails-you pill?

This idea came up a few years ago, and there’s no point in pretending that I wasn’t a bit skeptical of it:

This is a touchingly linear approach to drug therapy. It's actually kind of sweet. Since the authors clearly mean well, I won't wave my fists around too much. But I would like to point out that these things may well work a bit differently in combination than they do in less crowded company. I realize that many people take subsets of these, which is a good starting point, but taking all six at once will be a new adventure. Drug interactions aren't easy to predict, and that's putting it mildly. Some people are going to feel more effects of one part of the mixture, and some will get hit by another. Some of the people taking this monster will also be taking (for example) diabetes medication, which sets off a whole new set of possible interactions.

As I went on to mention in that post, though, the comments that came in to the British Medical Journal, where the original proposal appeared, were (in many cases) a lot nastier than what I had to say:

Some of the responses are favorable, but there are many that really unload on the authors and their idea. Phrases like "one the most egregious presentations that I have ever come across," "it is very dangerous to take bits and pieces of research and cobble it together," "I would like to add my voice to those who are truly dumbfounded," "total disregard for scientific principles" and "It is almost impossible to know where to start" are flying around over there.

Well, that was in the days before I had comment functions on this blog, so no one told me what they thought about my opinion. But now there are some results from just this sort of formulation, and I have to say, they’re not bad. Most of the beneficial results were about the same as the individual drugs (except for lowered triglycerides, where the effect was only about half as strong). And rather more surprisingly, there weren’t any complicating side effects or interactions. Cardiologists are quoted in the news articles as expressing surprise, and although I Am Not a Cardiologist, you can count me in there, too.

My biggest worry was actually getting all these things to absorb properly from the same pill – this thing must be interesting to manufacture. Medicinal chemists like me tend not to think much about excipients, binders, coatings, and the other issues that go into making solid pill formulations, but that stuff is not easy. There’s a lot of voodoo in it, too, since (after all) you’re trying to affect oral absorption, which is not a really well-understood process.

There's still no guarantee that the polypill, or some variation thereof, will make it. This is a first clinical look, and that's still a long way from the end. But it's already made it a bit further than I thought.

Comments (16) + TrackBacks (0) | Category: Cardiovascular Disease


1. MedChemMan on April 2, 2009 8:43 AM writes...

1) As the percentage of CV risk factor (high blood pressure, high blood chloesterol, and obesity) may vary from patient to patient, we may be required to have poly-pills with different compositions.
2) Diabetes is also one of the major CV risk factors. The scope of a poly-pill can be expanded by including even diabetes medication.

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2. Retread on April 2, 2009 9:39 AM writes...

As a neurologist, I hated Phelantin (a fixed combination of dilantin and phenobarbital -- two anticonvulsants) and never used it. All anticonvulsants are sedating to some extent (perhaps there are newer ones out since I retired which aren't, but I doubt it). Some people got more sedation on one than the other, so the dose of each required adjustment, impossible with Phelantin.

Granted that polypharmacy for epilepsy is to be avoided if possible, some individuals could not have their epilepsy controlled with a single drug without unacceptable sedation, while lower doses of two would work. Now that we know more about the distinct mechanisms by which anticonvulsants are thought to work (which we didn't in the 60s and 70s) we see why polypharmacy worked better in some cases of relatively drug resistant epilepsy.

The likelihood that there is a single optimal dose of each of the drugs in the mixture, good for all patients seems remote.

In favor of the idea -- patients (particularly the elderly with vascular disease of one form or other) ofteb have difficulty taking multiple pills correctly, and a single pill would make life easier for them and would improve compliance (always a problem).

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3. Chemjobber on April 2, 2009 10:19 AM writes...

I worked a little in formulations between college and grad school. There's a LOT of voodoo in it, but it's still pretty interesting stuff.

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4. Ben on April 2, 2009 11:22 AM writes...

I agree with all the comments above -- a polypill might work for something where we don't care as much about side-effects from drug-drug interactions (e.g. cancer) but for "lifestyle drugs" which require long term dosage in patients which are at risk for CV events, this doesn't strike me as a suitable approach for many diseases.

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5. milkshake on April 2, 2009 3:12 PM writes...

I am all for it and there would be a huge part of population that currently gets nothing and would benefit form taking it - but these are serious medications and I am worried that if introduced it will be given out by primary care docs like candy. You know - they spend 5 min with you, the nurse takes your blood pressure and asks how we are doing today - and off you go with a poly-pill prescription. This already is happening with statins and it has been going on with SSRIs for a long time. Almost every god-damned psychologist with an MS degree in cognitive behavioralism that gets the mental health job from HMO is now pushing these "safe" antidepressants - without being qualified to diagnose a major depression, bipolar disorder, schizophrenia or chronic fatigue syndrome; these things can appear remarkably similar.

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6. Michael on April 2, 2009 5:45 PM writes...

I'm pretty surprised, as these sorts of combinations always struck me as a terrible idea, mainly because it kills any bit of flexibility you had to tailor the individual drug doses.

Treximet is one such combination that really annoys me. Since Imitrex is (was) expensive to treat headaches, I'll take something like alleve first to see if that works. If it doesn't then I'll bring out the big guns. Combining naproxen and imitrex in the same pill (treximet) means that if you already took the alleve, you'll have to double up your dosage if you want the imitrex.

Never mind the moral dubiousness of combining an OTC headache med with a (now) generic headache med, and having the result getting new patent protection and costing 10x what the two pills do individually. I'm not sure if it's worse than the Nexium patent, but it's awfully close.

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7. chinabonding on April 2, 2009 6:47 PM writes...

My parents take multiple CV meds as mentioned. I wonder if it is a generational thing, but they would much rather save money and buy four generic pills than one premium pill. Guess it will depend on how good ones insurance is.

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8. drug_hunter on April 2, 2009 8:14 PM writes...

I get the convenience/compliance argument - it makes a lot of sense, and for the majority of patients the polypill will probably turn out to be a Good Thing for these reasons (at the expense of much higher cost). But aren't you just begging for problems? As other posters have noted, you lose all flexibility, plus you are almost definitely over-dosing many of the patients. (remember, 5 to 10 mgs of an ACE inhibitor or a statin is actually all most people need...) I would be really cautious.

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9. Michael on April 2, 2009 10:51 PM writes...

The multiple pill convenience factor doesn't even come into play with Treximet. When I've got a bad migraine, I would take ten pills the size of my thumb to make it go away. I'm not going to balk at two small pills.

The polypill is getting pushed because it's a naked cash grab to make unpatentable and already approved drugs into money makers again.

It's no better than taking the individuals, and I predict no significant improvements in compliance. If you're already taking a pill a day, why not two or five? Remembering to take one pill per day is the barrier, not additional ones.

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10. Smoki on April 3, 2009 2:33 AM writes...

I think there might be some psychological factor that would make people prefer the polypill, not the convenience.

If you take one pill a day, that's not too bad. If you have too swallow five or six of all kinds of colours and shapes, then you must really be seriously sick.

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11. drug_hunter on April 3, 2009 5:03 AM writes...

#9 and #10 - Sorry to disagree but in the Real World, compliance is an issue -- people make mistakes when taking their pills. Especially the elderly. I understand that for most of us, taking multiple pills isn't a problem. However, if you had a population of 100 people, all in their 70s, all taking 6 different medicines, you can bet the farm that at least a few of them are screwing up sometimes. Plus medicines come in different numbers of pills per bottle and some will run out before others. As a wise pharmacist once said to me, "Drug-hunter, never forget, there are a lot of confused and a few downright stupid people out there." So the potential compliance advantage of the polypill is genuine.

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12. Still Scared of Dinosuars on April 3, 2009 6:36 AM writes...

Compliance is always an issue. It's an issue in clinical trials where people have weekly doctor visits, return all the unused meds from the previous week (which are counted to measure compliance), and are given a fresh new bottle for the next seven days. It's an issue when people are in nursing homes and are given the meds by nurses every day. Thinking it's not an issue in the real world is silly.

As far as dosages go one question is how far are the ranges of safe and effective doses for the individual meds. The most likely scenarion I imagine wherein the polypill would be effective would be when all of its constituent meds are in essence background meds to a primary condition such as for cardiovascular risk in diabetes patients. The polypill might be used for blanket reduction of such risk while the useage of drugs and other treatments for the diabetes are optimized. Such a pill would require meds that have a clear range of "pretty likely to help, very unlikely to harm" doses. Maybe there aren't enough such meds to make it work>

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13. David on April 3, 2009 3:11 PM writes...

Here's the problem with this one..... It contains aspirin.

A man's scheduled for nasal septum surgery. "I take it that you don't take any aspirin?" "Oh, no, I don't take any aspirin! I just take medicine for my blood pressure and cholesterol" he undergoes surgery and has a terrible post-op nosebleed. Or, it can all kinds of elective surgery,... post arthoscopy bleeding, post TURP bleeding, Post dental extraction bleeding. People will 'forget' that they are on aspirin and fail to stop taking it 7 days before an elective operation..... or, they will stop it and find out on the day of surgery that their blood pressure, previous well controlled, is now 170/95.


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14. Sili on April 4, 2009 5:58 PM writes...

Re compliance: does anyone know if the individual packaging at pharmacies actually work?

By that I mean the automated wrapping of one persons medicines in clearly marked blisterpacks so that it's one just has to pop open the relevant blister morning, noon and night.

And for the love of God, Montresor, someone close that runaway italics tag.

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15. Steve Parker, M.D. on April 4, 2009 7:51 PM writes...

Full disclosure: I haven't read the full Indian study referenced above.

Nevertheless... Note that the study involved only about 2000 people and studied them for only 12 weeks. How many strokes and heart attacks would you expect to see in twelve weeks. Very few. In some 12-week periods you wouldn't see ANY.

I suspect the results are due to chance alone, or other mischief. But I'm not a statistician, so take this with a grain of salt. I hope Sandy at analyzes this study for us.

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16. Horace S. Patoot on April 7, 2009 9:29 AM writes...

It's an old idea in pharmacy:

I was not long since in a company where I wot not who of my fraternity brought news of a kind of pills, by true account, composed of a hundred and odd several ingredients; whereat we laughed very heartily, and made ourselves good sport; for what rock so hard were able to resist the shock or withstand the force of so thick and numerous a battery?

(Michel de Montaigne (1533-1592), French essayist. "Of the Resemblance Between Children and Fathers," bk. 2, ch. 37, Essays, trans. by John Florio (1588).)

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