Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping

OBJECTIVES: Determination of hepatic and intestinal cytochrome P450 (CYP) 3A activity is important, because CYP3A substrates show substantial variability in plasma concentrations as a result of variations in both hepatic and intestinal metabolism. The goals of this study were (1) to determine whether the hepatic and intestinal extraction ratios (ER(H) and ER(G), respectively) of the CYP3A probe drug midazolam are different when determined after semisimultaneous administration, as compared with administration on separate occasions (traditional method), and (2) to evaluate the hepatic and intestinal metabolism of midazolam in the presence and absence of ketoconazole by the semisimultaneous method. METHODS: Midazolam pharmacokinetics was assessed in 12 healthy volunteers after administration of midazolam, 5 mg orally, followed at 6 hours by 2 mg given by intravenous infusion. Concentration-time data were fitted to a combined oral-intravenous infusion model by nonlinear regression (semisimultaneous method). Data from the semisimultaneous method were compared with those obtained after individual midazolam doses, 1 week apart (traditional approach). The effect of ketoconazole on midazolam pharmacokinetics after semisimultaneous administration was also determined in 4 healthy volunteers. RESULTS: There were no significant differences in bioavailability (0.343 +/- 0.100 versus 0.343 +/- 0.094), ER(H) (0.269 +/- 0.064 versus 0.267 +/- 0.077), and ER(G) (0.534 +/- 0.135 versus 0.531 +/- 0.124) between the traditional and semisimultaneous methods. As expected, ketoconazole markedly increased the mean bioavailability to 0.838 (2.4-fold), the mean ER(H) was decreased 3.7-fold, and the mean ER(G) was decreased 5.7-fold. CONCLUSIONS: Midazolam pharmacokinetic parameters that are specific to liver and intestinal metabolism were not different between the traditional and semisimultaneous methods. The semisimultaneous method also yielded expected marked changes in the parameters as a result of ketoconazole inhibition. Thus the semisimultaneous midazolam method appears to be a suitable approach to determine hepatic and intestinal CYP3A activity at baseline and with enzyme inhibition.     

New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http://www.fda.gov/cder/drug/drugInteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling.