Semiphysiologically based pharmacokinetic models for the inhibition of midazolam clearance by diltiazem and its major metabolite

Xin Zhang, Sara Quinney, J. Christopher Gorski, David R. Jones, Stephen D. Hall

Research output: Contribution to journalArticle

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Abstract

Prediction of the extent and time course of drug-drug interactions (DDIs) between the mechanism-based inhibitor diltiazem (DTZ) and the CYP3A4 substrate midazolam (MDZ) is confounded by time-and concentration-dependent clearance of the inhibitor. Semi-physiologically based pharmacokinetic (PBPK) models were developed for DTZ and MDZ with the major metabolite of DTZ, N-desmethyldiltiazem (nd-DTZ), incorporated in the DTZ model. Enzyme kinetic parameters (k inact and KI) for DTZ and nd-DTZ were estimated in vitro and used to model the time course of changes in the amount of CYP3A4 in the liver and gut wall, which in turn, determined the nonlinear elimination of MDZ and DTZ, and the corresponding DDI. The robustness of the model prediction was assessed by comparing the results of the prediction to published DTZ pharmacokinetic and DTZ/MDZ interaction data. A clinical study was conducted to further validate the predicted increase of MDZ exposure after DTZ treatment. The model predicted the non-linear disposition of DTZ after single and multiple oral doses. The clinical study showed that DTZ treatment resulted in 4.1- and 1.6-fold increases in MDZ exposure after oral and intravenous MDZ administration, respectively, suggesting that the DDI in the gut wall plays an important role in the DTZ/MDZ interaction. The semi-PBPK model incorporating the DDI at the gut wall, and the effect of nd-DTZ successfully predicted the nonlinear disposition of DTZ and its interaction with MDZ. Moreover, model simulation suggested that both DTZ and nd-DTZ contributed to the overall inhibitory effect after DTZ administration, and the values of the in vitro estimated inhibition parameters and CYP3A4 turnover rate are critical for the prediction.

Original languageEnglish
Pages (from-to)1587-1597
Number of pages11
JournalDrug Metabolism and Disposition
Volume37
Issue number8
DOIs
StatePublished - Aug 2009

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Diltiazem
Midazolam
Pharmacokinetics
Drug Interactions
Cytochrome P-450 CYP3A
Pharmaceutical Preparations
Nonlinear Dynamics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Semiphysiologically based pharmacokinetic models for the inhibition of midazolam clearance by diltiazem and its major metabolite. / Zhang, Xin; Quinney, Sara; Gorski, J. Christopher; Jones, David R.; Hall, Stephen D.

In: Drug Metabolism and Disposition, Vol. 37, No. 8, 08.2009, p. 1587-1597.

Research output: Contribution to journalArticle

Zhang, Xin ; Quinney, Sara ; Gorski, J. Christopher ; Jones, David R. ; Hall, Stephen D. / Semiphysiologically based pharmacokinetic models for the inhibition of midazolam clearance by diltiazem and its major metabolite. In: Drug Metabolism and Disposition. 2009 ; Vol. 37, No. 8. pp. 1587-1597.
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