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Hello,
I have a question regarding a phenomenon I'm seeing with steady-state
vs. single dose data.
After multiple doses of a pro-drug, the Cmax and AUC of the active
component at steady-state decreases compared with single dose
administration. There are no changes in T1/2 or Tmax.
Does anyone know of other drugs that display a similar change? What
mechanisms could potentially explain this?
Please let me know if additional information is required for your
thoughtful input.
Many thanks in advance,
MLH
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The following message was posted to: PharmPK
Dear MLH,
I am assuming that you are administering your pro-drug orally. One
possible explanation of what you observe is the induction of enzymes,
either in the gut wall or the liver. If your drug is a "high extraction"
compound, an induction would not change its elimination half-life
significantly but result in marked decrease in its bioavailability.
Artemisinin, an antimalarial drug, shows similar properties. Just do a
Pubmed search for artemisinin + autoinduction and you will find several
articles. If you have PK data that you plan to model, take a look at
Gordi et al., Br J Clin Pharmacol. 2005 Feb;59(2):189-98. I would be
more than happy to provide the NONMEM control stream for the
autoinduction model presented in that paper. You may also contact me
directly if you need more help.
Toufigh Gordi, PhD
Associate Director of Pharmacokinetics
1360 O'Brien Drive
Menlo Park, CA 94025-1436
USA
Phone: 650-462-2752 ext. 273
Fax: 650-462-9993
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The following message was posted to: PharmPK
Dear MLH,
Bosentan, an endothelin receptor antagonist approved for the
treatment of
pulmonary arterial hypertension, has such a profile (for review see
Dingemanse and van Giersbergen, Clin Pharmacokinet
2004;43:1089-1115). For
bosentan all available evidence point towards autoinduction of
metabolizing
enzymes as the mechanism.
Regards
Paul van Giersbergen, PhD
Actelion Pharmaceuticals Ltd.
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