Hi, why is AUC7d-last included in the FDA leuprolide development guidance?
I tried to find out by myself but I couldn't...
Thank you.
Hi,
In the text of guidance FDA state “Note that leuprolide acetate for depot suspension (….) is the subject of two separate reference products.” For example, some drugs (LUPANETA PACK) contain leuprolide acetate and norethindrone acetate. From another document, we can find that “Drugs or herbal products that induce or inhibit certain enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone.” On one hand, norethindrone is a CYP3A4 substrate and from another hand, leuprolide causes a transient increase in serum concentrations of testosterone during the first week of treatment (“flare-up” effect). Consequently, may impact norethindrone concentration in blood plasma depending on this specific pharmacodynamic effect because the metabolism of testosterone (testosterone 6beta-hydroxylation) is ongoing by CYP3A4/5 as well.
In conclusion, this effect (impact on testosterone concentration in blood plasma) could make the first week of PK highly variable and make the analysis inconsistent so AUC(7-t) in some cases (combined drugs) could be more valuable than AUC(0-t).
Some useful links please find below:
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021343s030,021379s030,021488s027,021731s027lbl.pdf
- https://clinicaltrials.gov/ct2/show/NCT04783636
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203696s001lbl.pdf
Article Pharmacokinetic–Pharmacodynamic Model for the Testosterone-S...
Best regards,
Tomasz
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