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Research ArticleArticle

Statistical Methods for Analysis of Time-Dependent Inhibition of Cytochrome P450 Enzymes

Phillip Yates, Heather Eng, Li Di and R. Scott Obach
Drug Metabolism and Disposition December 2012, 40 (12) 2289-2296; DOI: https://doi.org/10.1124/dmd.112.047233
Phillip Yates
PharmaTherapeutics Statistics, Pfizer Inc., Groton, Connecticut (P.Y.); and Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (H.E., L.D., R.S.O.)
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Heather Eng
PharmaTherapeutics Statistics, Pfizer Inc., Groton, Connecticut (P.Y.); and Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (H.E., L.D., R.S.O.)
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Li Di
PharmaTherapeutics Statistics, Pfizer Inc., Groton, Connecticut (P.Y.); and Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (H.E., L.D., R.S.O.)
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R. Scott Obach
PharmaTherapeutics Statistics, Pfizer Inc., Groton, Connecticut (P.Y.); and Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (H.E., L.D., R.S.O.)
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Abstract

Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes, especially CYP3A4, is an important attribute of drugs in evaluating the potential for pharmacokinetic drug-drug interactions. The analysis of TDI data for P450 enzymes can be challenging, yet it is important to be able to reliably evaluate whether a drug is a TDI or not, and if so, how best to derive the inactivation kinetic parameters KI and kinact. In the present investigation a two-step statistical evaluation was developed to evaluate CYP3A4 TDI data. In the first step, a two-sided two-sample z-test is used to compare the kobs values measured in the absence and presence of the test compound to answer the question of whether the test compound is a TDI or not. In the second step, kobs values are plotted versus both [I] and ln[I] to determine whether a significant correlation exists, which can then inform the investigator of whether the inactivation kinetic parameters, KI and kinact, can be reliably estimated. Use of this two-step statistical evaluation is illustrated with the examination of five drugs of varying capabilities to inactivate CYP3A4: ketoconazole, erythromycin, raloxifene, rosiglitazone, and pioglitazone. The use of a set statistical algorithm offers a more robust and objective approach to the analysis of P450 TDI data than frequently employed empirically derived or heuristic approaches.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.047233.

  • ABBREVIATIONS:

    TDI
    time-dependent inhibition
    DDI
    drug-drug interaction
    DMSO
    dimethyl sulfoxide
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    P450
    cytochrome P450
    RMSE
    root mean square error.

  • Received June 13, 2012.
  • Accepted August 31, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (12)
Drug Metabolism and Disposition
Vol. 40, Issue 12
1 Dec 2012
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Research ArticleArticle

STATISTICAL ANALYSIS OF TIME-DEPENDENT INHIBITION DATA

Phillip Yates, Heather Eng, Li Di and R. Scott Obach
Drug Metabolism and Disposition December 1, 2012, 40 (12) 2289-2296; DOI: https://doi.org/10.1124/dmd.112.047233

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Research ArticleArticle

STATISTICAL ANALYSIS OF TIME-DEPENDENT INHIBITION DATA

Phillip Yates, Heather Eng, Li Di and R. Scott Obach
Drug Metabolism and Disposition December 1, 2012, 40 (12) 2289-2296; DOI: https://doi.org/10.1124/dmd.112.047233
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