E-DRUG: Norgestrel and combined contraceptive pills (cont'd)

[John Urquhart <urquhart@netcom.com>]

E-drug: Norgestrel and combined contraceptive pills (cont'd)
---------------------------------------------

Dear Gaut,

I reviewed the American labeling for labetolol, which, though it cautions 
against the drug's use in patients with impaired liver function, takes 
none of the usual steps of boxed warnings or use of bold-faced type to 
designate special hazards.  It also clarifies the number I was vague 
about in my initial note, namely that there are 4 optically active 
isomers comprising labetolol, one of which is dilevalol.  So here we have 
a situation where one of the four isomers has turned out to pose an 
unacceptable risk of hepatotoxicity when given in pure form.  This same 
agent comprises one-quarter of the dose of labetolol, an agent with a 
record of safety-in-use that has not prompted special warnings against 
hepatotoxicity during many years of use.  On the face of it, this finding 
is a challenge to the often-repeated sloganeering about the a priori 
desirability of using optically pure isomers.   It is a challenge that 
cannot be dismissed simply on the basis of the ostensibly higher dose of 
dilevalol used in that product, compared to what is present in the 
standard dose of labetolol, given, as I noted earlier, that 
weight-independent dosing gives a 3 or more to 1 diversity in drug 
exposure due to variations in body weight, plus a further diversity of 
2-4 fold due to between-patient differences in pharmacokinetic 
parameters.   So the question at issue, I believe, is: does the 
supposedly inactive optical isomer confer some degree of protection 
against the actions of the other isomer?   It is a question to be 
answered, not by debate, but by experimental analysis of interactions 
between the two optical isomers of various clinically useful racemic 
mixtures, and by meta-analysis of the often-repeated proposition that 
racemic mixtures are inferior to use of optically pure isomers.  As has 
often occurred in clinical pharmacology and therapeutics, pretty theories 
are eventually undone by ugly facts.  One's choice of terms can often 
block progress, e.g., "inert" ingredients, "physiological" saline, "safe" 
drugs, and the like.

A further aspect of the norgestrel story is that it is the active 
ingredient in NORPLANT, the 5-year implant subcutaneous implant form, 
which, as I noted in a recent review of drug delivery systems*, has the 
highest level of contraceptive efficacy of any of the steroidal 
contraceptives, whereas oral forms of norgestrel (the so-called 
'minipill') have the poorest level of contraceptive efficacy of any of 
the steroidal contraceptives.  The difference, of course, is the assured 
continuity of exposure to norgestrel in the case of NORPLANT, whereas the 
daily oral form requires not only consistent daily dosing, but precise 
timing of the daily dose, because the agent's contraceptive action lasts 
for an estimated 27 hours after the last-taken dose, which means only a 
3-hour average margin for error in the timing of the next-taken dose.  

* Urquhart J.  Can delivery systems deliver value in the new 
pharmaceutical marketplace?  Br J Clin Pharmacol 44: 413-419, 1997.

John Urquhart
University of Maastricht, The Netherlands
rquhart@netcom.com
--
Send mail for the `E-Drug' conference to `e-drug@usa.healthnet.org'.
Mail administrative requests to `majordomo@usa.healthnet.org'.
For additional assistance, send mail to:  `owner-e-drug@usa.healthnet.org'.