E-drug: Norgestrel and combined contraceptive pills (cont'd)
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The whole question of racemic mixtures is more complex than meets the
eye. On theoretical grounds, one can argue that the supposedly
inactive isomer ought to be gotten rid of, and only the active one used
for treatment. The key term, however, is 'supposedly inactive',
evidence for which is a molecule by molecule story. A cautionary tale
is provided by the Glaxo agent, labetolol, which has either two or four
optically active sites, and is thus a multiple racemic mixture. One of
those optical isomers turned out to have a favorable profile as a beta
receptor antagonist, and was patented and developed by the US firm
Schering-Plough as a pharmaceutical. My memory, if it isn't playing
tricks, is that the name of the agent was levobunolol. It was registered
first in Portugal and Japan and put on the market in those two
countries; meanwhile it had gone through the advisory cte review at
FDA where some concerns had been voiced about hepatotoxicity. After
less than a year in the Portuguese and Japanese markets, it was
withdrawn because of unacceptably high rates of hepatotoxicity, which
was the end of the story for levobunolol. All this happened sometime in
the past decade.
But what of labetolol, which was either 1/8th or 1/4th composed of
levobunolol, together with the dextro isomer (supposedly inactive) plus
the other constituents? In its many years of use as a combined
alpha-beta blocker, labetolol has had an ostensibly satisfactory adverse
reaction record. You could say that this comes about because of the
relatively low does of the levobunolol constituent, but consider several
facts about the actual levels of exposure to that constituent: (a) no
one does weight-adjusted dosing with labetolol, so small people get the
same dose as big people, and so the small people have correspondingly
higher plasma levels of drug; (b) there is the usual range of variance
in pharmacokinetic parameters. So, if you consider the outliers -- the
smallest sized patients with the lowest PK clearance values -- you'll
end up with levobunolol levels during labetolol use that are arguably
in the range they fell in the market experience with levobunolol as a
stand-alone agent. It leaves one contemplating the question: does the
d-isomer play a protective role?
There are, meanwhile, several companies that have staked their futures
on separations technologies for isolating the l- or d- isomer from the
fairly wide array of racemic mixture pharmaceuticals in the
marketplace. They of course believe that such separations are the path
to safer, more effective pharmaceuticals, but it is an assumption that
needs to be tested, case by case. The whole area is ripe for a careful,
thoughtful meta-analysis, informed by modeling both at the molecular
level and at the PK/PD level.
In thinking further about my comments regarding the optical isomers
within labetolol, I think that the name of the isomer developed by
Schering-Plough, and then removed from the market because of
hepatotoxicity, was dilevalol, not levobunolol. Or, let's say it's on of
the two. I'm in The Netherlands at the moment and my notes on this
topic are in California.
John Urquhart, M.D.
Prof. of Pharmaco-epidemiology
Maastricht University
Maastricht, NL
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