“Woah! It's like Spotify but for academic articles.”

Instant Access to Thousands of Journals for just $40/month

Get 2 Weeks Free

Quantitative Evaluation of Pharmacokinetic Inhibition of CYP3A Substrates by Ketoconazole: A Simulation Study

Quantitative Evaluation of Pharmacokinetic Inhibition of CYP3A Substrates by Ketoconazole: A Simulation Study

Abstract

The US Food and Drug Administration draft drug interaction guidance recommends that 400 mg ketoconazole (KTZ) be administered once daily for several days (QD400) for maximal CYP3A inhibition. Some investigators suggest that a single dose of 400 mg (SD400) KTZ is sufficient given its short half-life (t 1/2 ~ 3-5 hr). To determine the impact of KTZ regimens on CYP3A inhibition, we simulated AUC fold-change (AUCR) in the presence of SD400, QD400, or 200 mg twice-daily (BID200) KTZ for theoretical CYP3A substrates. Ratios of AUCR (AUCR QD400 /AUCR SD400 and AUCR BID200 AUCR QD400 ) increase with increasing bioavailability and increasing substrate t 1/2 . The SD400 KTZ regimen may provide maximal inhibition only for a subset of substrates (ie, low bioavailability and short t 1/2 ). For substrates with t 1/2 longer than that of KTZ, multiple KTZ dosing is critical and BID200 appears to provide greater inhibition than QD400. Also, timing of KTZ administration should be optimized to allow maximal presystemic enzyme inhibition prior to substrate administration.
Loading next page...
Problems Reading this Article? Report Issue Here
 
/lp/sage/quantitative-evaluation-of-pharmacokinetic-inhibition-of-cyp3a-ycx860y2rr

You're reading a free preview. Subscribe to read the entire article.

And millions more from thousands of peer-reviewed journals, for only $40/month.

Get 2 Weeks Free

To be the best researcher, you need access to the best research

  • With DeepDyve, you can stop worrying about how much articles cost, or if it's too much hassle to order — it's all at your fingertips. Your research is important and deserves the top content.
  • Read from thousands of the leading scholarly journals from Springer, Elsevier, Nature, IEEE, Wiley-Blackwell and more.
  • All the latest content is available, no embargo periods.

Stop missing out on the latest updates in your field

  • We’ll send you automatic email updates on the keywords and journals you tell us are most important to you.
  • There is a lot of content out there, so we help you sift through it and stay organized.