Corante

About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

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: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Oh, Come On | Main | Elbow Room »

August 28, 2007

Like Clockwork

Email This Entry

Posted by Derek

There are a lot of drug development issues that people outside the field (and beginning medicinal chemists) don't think about. A significant one that sounds trivial is how often your wonder drug is going to be taken.

Once a day is the standard, and it's generally what we shoot for unless there's some reason to associate the drug with meals, sleep/wake cycles, or the like. People can remember to take something once a day - well, they remember it better than most of the other dosing schedules, anyway. That's why you actually want your compounds to be metabolized and cleared - everything has to be ready for the next dose tomorrow.

If your compound has a long half-life in the body after dosing, you'll step on the tail end of the last dose and you can see gradual accumulation of the drug in plasma or other tissues. And that's almost always a bad thing, because eventually every drug in the world is going to do something that you don't want. All you have to do is get the concentration up too high for too long (and figuring out what's too high and what's too long is the one-sentence job description of a toxicologist). If you stairstep your way up with accumulating doses, you'll get there in the end.

Ah, you might say, then just take the drug every other day. Simple! Sorry. Every other day (or every three, or four) is a complete nightmare for patient compliance. People lose track, and doctors know it. You'd better have a really compelling reason to go ahead with a weird regiment like that, and if you do, someone's going to seize the chance to come into your market with a once-a-day as soon as they can find one. (The exceptions to this are drugs given in a clinic, like many courses of chemotherapy - but in those cases, someone else is keeping track).

How about more often than once a day (q.d., in the Latin lingo). Well, twice a day (b.i.d. can work if it's morning/night. Three times a day can go with meals, presumably, but people are going to get tired of seeing your pills. More than three times a day? There'd better be a reason, and it had better be good.

So don't be scared as you watch your compounds disappear after giving them to the animals. You want that. Just not too quickly, and not too slowly, either.

Comments (19) + TrackBacks (0) | Category: Drug Development | Pharma 101 | Pharmacokinetics


COMMENTS

1. MolecularGeek on August 28, 2007 10:30 PM writes...

One a day is bad enough if you are trying to ensure that it's a regular 24 hour cycle between doses. When you start trying to tie it to food intake or sleep cycle, that gets ugly and if your miracle compound has really tight PK AND needs to be taken with a specific kind of food (high fat content, for sake of argument) you are just asking for compliance failures left and right. I know someone who is on HIV protease inhibitors, and the hassle of arranging his life to make sure that sometime between 5:30 and 6:30 in the evening he gets a sufficient bolus of a high-fat food into his stomach to take with THE PILL is considerable. My takeaway is to try for once a day dosing with a little leeway in timing, but given the choice between once a day with strict requirements for administration and 2 or 3 doses a day with nothing more required than "take with food" or "take on an empty stomach", I'd gladly set an alarm for the latter.

MG

Permalink to Comment

2. Chrispy on August 28, 2007 11:18 PM writes...

Interesting in this regard is Reclast, Novartis's once-per-year osteoperosis infusion. It is a bisphosphonate with, from what I understand, the same liabilities.

I like a drug I can stop taking if something goes awry. One year? Scares the bejesus out of me!

Permalink to Comment

3. Still Scared of Dinosaurs on August 29, 2007 7:51 AM writes...

These issues affect trial design and conduct but it's hard to get all the bugs in the regimen worked out there. For example, some drugs can be allowed to build up to fully active levels, but in trials that may mean multi-dose PK which is costly to perform and difficult to nail down especially if you don't have really unambiguous efficacy measures. Even tracking patient compliance in the course of a trial is error prone. Sometimes it's just pill counts, other times it's patient diaries, but you're never really sure how accurate the data are. What you can be sure of is that whatever compliance problems you encounter in trials will be worse in the real world.

Permalink to Comment

4. MTK on August 29, 2007 8:13 AM writes...

Crispy,

One a year is actually great. You go to the doctor, you take it. You don't even have to have it home.

I don't know if anyone has ever done it, but if you had a every other day or every three day format, one could package it like birth control is packaged in 30 day blister packs with every other day being a placebo. That would probably increase patient compliance. Of course, that means a greater cost.

Permalink to Comment

5. HelicalZz on August 29, 2007 8:32 AM writes...

Good commentary.

It does bring to mind the recent trial of Coreg CR where GSK attempted to show improved compliance with it's slow release formulation of (soon to be off patent) carvedilol. [OK if I call this a marketing trial rather than a clinical trial]. They found no significant increase in compliance for the once-a-day Coreg CR over the twice-a-day old formulation.

Going to make justifying the extra $$ for the CR (controlled release) version a bit tougher to swallow. At least for the insurance companies (pun intended).

Zz

Permalink to Comment

6. Clark Kent on August 29, 2007 9:24 AM writes...

The bisphosphonates are a special case. They actually have a significant side effect of acid reflux when the pill is taken, and it is recommended patients remain upright for 1 hour after taking. For people with osteoperosis this can be a significant liability. Thats why less frequent dosing is desirable in this case, hence the once weekly, once monthly, and once quarterly pills and once yearly infusion that have been introduced in the last couple years to compete with a once daily pill.

Permalink to Comment

7. Kay on August 29, 2007 9:51 AM writes...

Much to our fortune, we have sophisticated tools that allow us to choose the correct compound for development. Hurray for Rules and bond counts! Let's not tell management that our jobs are so easy.

Permalink to Comment

8. CMC guy on August 29, 2007 10:21 AM writes...

The concept of once a day is a good rule of thumb but for dosing ultimately many factors seem to come in to play. The "fun" of drug development kicks in after discovery. What's seen in animal PK models doesn't always translate well to people and initial development phase in a jump although relative trends often hold up so can aid choice of candidate (I think I recall survey a few years ago say something like >90% of Drug failures due to ADME). Formulators can sometimes tweak things to get a better profile particularly if good starting factors (although rare to overcome really bad bioavailability/clearance). The disease target and other treatments influence acceptability as to Dinosaurs point about trial design. Usually the Marketing/Sales folks want to balance ease/acceptability and profits (usually heavy toward second). I am biased but typically Manufacturing, who is often under pressure just to keep up the flow of supply, gets squeezed between Clinical and Marketing who want different things.

Permalink to Comment

9. Anne on August 29, 2007 10:39 AM writes...

Perhaps this is a dumb question — I'm not a chemist — but what's wrong with taking a drug more often in smaller doses? I mean, if a drug washes out of the body in a week and I need to take 70 mg/week (say), why not take 10 mg/day? I get the same amount in my bloodstream after the first week, in fact there's less variation, so what's the problem?

Permalink to Comment

10. 7374e9 on August 29, 2007 11:59 AM writes...

What's wrong with arranging your life around drug dosing - one is not taking a candy, it's a drug to help with one's disease! Especially something like HIV...

Permalink to Comment

11. weirdo on August 29, 2007 12:05 PM writes...

(70 mg/week vs. 10 mg/day).

It's all about coverage and maximal exposure and half-life. If your PK is linear, and the half-life is 4 days, then the half-life of each 10 mg dose is 4 days. Thus, daily 10-mg doses will not give you the same profile as a single 70 mg dose weekly (different maximum exposure with seven separate peaks, as opposed to a higher, but single, maximum exposure). And, as Derek noted in his original post, blood levels will theoretically continue to rise until they reach steady-state which, for a 4-day half-life, would take a mighty long time.

This, of course, is the basis for extended release. It is possible to "fix" a short half-life drug with formulation, an option not available to a long half-life drug.

Permalink to Comment

12. Bystander on August 29, 2007 3:47 PM writes...

Amiodarone is the one drug I can think which is useful despite having an inconveniently long half-life, approx 48 days. Whether it would ever get to market now is another matter.

Permalink to Comment

13. Anonymous on August 29, 2007 7:15 PM writes...

"What's wrong with arranging your life around drug dosing - one is not taking a candy, it's a drug to help with one's disease!"

The evidence shows that most people are willing to trade years of life expectancy in exchange for eating when they want and occassionally sleeping in. When it is a matter of immediate certain death (HIV), most first world people are willing to pay thousands of dollars a year extra to get reasonable dosing schedules and interactions.

"I mean, if a drug washes out of the body in a week and I need to take 70 mg/week (say), why not take 10 mg/day?"

It depends on what you want to accomplish. If you want full blood levels NOW and fast removal at the end of treatment (antibiotic), that does not work. If you want gentle onset and gentle withdrawal (antiepileptics, antidepressants), that works like a charm and in fact several successful drugs do that.

Permalink to Comment

14. Polymer Bound on August 29, 2007 7:41 PM writes...

MTK: I disagree... if the drug has a -spotless- safety profile, once a year works. If you're the one in a thousand that has an adverse reaction, a drug like that can really ruin your life.

This happened to a friend of my family, with a bisphosphonate actually. She was on a more frequent dosing regimen and "asked her doctor" about the once a month option. Now she can't move. Yay direct marketing.

Permalink to Comment

15. RKN on August 29, 2007 8:29 PM writes...

Ah, you might say, then just take the drug every other day. Simple! Sorry. Every other day (or every three, or four) is a complete nightmare for patient compliance. People lose track, and doctors know it.

I wonder if programmed drug delivery through the skin is a way to solve the patient compliance problem. Looks like it's doable for lower molecular weight drugs, and with continued technological improvements maybe this will be all the rage before long?

Permalink to Comment

16. MTK on August 30, 2007 7:15 AM writes...

Polymer bound,

I was talking from simply a patient compliance standpoint, which is usually the major issue with anything that isn't u.i.d.

Permalink to Comment

17. tgibbs on August 30, 2007 1:32 PM writes...

As long as elimination is first order, the drug won't accumulate indefinitely, even if you are "stepping on the tail" of the last dose--it will eventually reach an approximate steady state. So you can simply scale down the dose so that at steady-state it just kicks the blood levels back up to your desired peak. There is even an advantage in that the blood levels will be more stable between doses than with a short-acting drug, which is important if you need continuous action. The downside is that giving a steady-state dose of a long-acting drug means it will take quite a while to build up to a therapeutic level, so you may need to start out with a higher loading dose.

Permalink to Comment

18. Anonymous BMS Researcher on August 31, 2007 12:50 PM writes...

tgibbs, such considerations are part of the reason with some drugs we tell the patient, take two tablets now, then one per day thereafter until they're gone.

Permalink to Comment

19. Jonadab the Unsightly One on September 26, 2007 8:41 AM writes...

Heh. Indeed. If you can come up with a hypothyroid medication that can be taken any old time of day and doesn't require an empty stomach when taken (and for about an hour afterwards), patients will rise up and call you blessed.

Regarding blister-packs and placebo for improving patient compliance on every-n-days dosing, I'm not really sure. I mean, I'm sure it would work pretty well for some patients, but with the popularity of those little plastic day-by-day pill cases (the ones you refill weekly with all your different pills, and then each morning/evening/whenever you just open the appropriate little labelled box and take those ones) I would worry that the pills might get out of order for some patients. There's also the question of how many to package in a given blister-pack, because insurance companies typically don't want patients to get their next batch of pills too soon after the previous batch (much less than a month and things get ugly), but patients on multiple medications like to work things out so they can go pick up several different prescriptions on the same day, even if they didn't start them on the same day, so they often want to pick up more than thirty days' worth at once, and if not there's a risk that they'll misplace some days to get things to work out. It would be tempting to package a sixty-day regimen.

> What's wrong with arranging your life around drug dosing

People just don't want to do it.

In fact a lot of people would pretty much rather die than have to rearrange their lives. Indeed, there are whole categories of drugs that people take mostly to *avoid* having to rearrange their lives around medical concerns. Lipitor and Glucophage spring immediately to mind: most of the people taking those could completely avoid the need for them by rearranging their diet, but they are unwilling to do that.

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
XKCD on Protein Folding
The 2014 Chemistry Nobel: Beating the Diffraction Limit
German Pharma, Or What's Left of It
Sunesis Fails with Vosaroxin
A New Way to Estimate a Compound's Chances?
Meinwald Honored
Molecular Biology Turns Into Chemistry
Speaking at Northeastern