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0090-9556/03/3107-815-832$20.00
DMD 31:815-832, 2003

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PERSPECTIVE

THE CONDUCT OF IN VITRO AND IN VIVO DRUG-DRUG INTERACTION STUDIES: A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) PERSPECTIVE

Thorir D. Bjornsson, John T. Callaghan, Heidi J. Einolf, Volker Fischer, Lawrence Gan, Scott Grimm, John Kao, S. Peter King, Gerald Miwa, Lan Ni, Gondi Kumar, James McLeod, R. Scott Obach, Stanley Roberts, Amy Roe, Anita Shah, Fred Snikeris, John T. Sullivan, Donald Tweedie, Jose M. Vega, John Walsh, and Steven A. Wrighton

Abbott Laboratories, Abbott Park, Illinois (S.R.), Amgen Inc., Thousand Oaks, California (G.K., J.T.S.), AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (S.G.), Aventis, Bridgewater, New Jersey (S.P.K.), Bayer Corporation, West Haven, Connecticut (A.S.), Boehringer Ingelheim Corporation, Ridgefield, Connecticut, (D.T.), Eli Lilly and Company, Indianapolis, Indiana (J.T.C., L. N., S.A.W.), GlaxoSmithKline, Research Triangle Park, North Carolina (J.W.), Merck Research Laboratories, West Point, Pennsylvania (J.M.V.), Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (L.G., G.M.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (H.J.E., V.F., J.M.), Pfizer Inc., Groton, Connecticut (R.S.O.), Procter & Gamble, Cincinnati, Ohio (A.R.), Sanofi-Syntelabo Inc., Malvern, Pennsylvania (F.S.), Wyeth, Collegeville, Pennsylavnia (T.D.B., J.K.)

Abstract

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.


Address correspondence to: Volker Fischer, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07836-1080. E-mail: volker.fischer{at}pharma.novartis.com




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The Annals of PharmacotherapyHome page
K. A Bachmann and J. D Lewis
Predicting Inhibitory Drug-Drug Interactions and Evaluating Drug Interaction Reports Using Inhibition Constants
Ann. Pharmacother., June 1, 2005; 39(6): 1064 - 1072.
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Drug Metab. Dispos.Home page
M. Zhu, W. Zhao, H. Jimenez, D. Zhang, S. Yeola, R. Dai, N. Vachharajani, and J. Mitroka
CYTOCHROME P450 3A-MEDIATED METABOLISM OF BUSPIRONE IN HUMAN LIVER MICROSOMES
Drug Metab. Dispos., April 1, 2005; 33(4): 500 - 507.
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J Clin PharmacolHome page
E. D. Kharasch, A. Walker, C. Hoffer, and P. Sheffels
Evaluation of First-Pass Cytochrome P4503A (CYP3A) and P-Glycoprotein Activities Using Alfentanil and Fexofenadine in Combination
J. Clin. Pharmacol., January 1, 2005; 45(1): 79 - 88.
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Drug Metab. Dispos.Home page
J. A. Williams, R. Hyland, B. C. Jones, D. A. Smith, S. Hurst, T. C. Goosen, V. Peterkin, J. R. Koup, and S. E. Ball
DRUG-DRUG INTERACTIONS FOR UDP-GLUCURONOSYLTRANSFERASE SUBSTRATES: A PHARMACOKINETIC EXPLANATION FOR TYPICALLY OBSERVED LOW EXPOSURE (AUCI/AUC) RATIOS
Drug Metab. Dispos., November 1, 2004; 32(11): 1201 - 1208.
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J Clin PharmacolHome page
N. G. B. Agrawal, C. Z. Matthews, R. S. Mazenko, E. J. Woolf, A. G. Porras, X. Chen, J. L. Miller, N. Michiels, M. Wehling, A. Schultz, et al.
The Effects of Modifying In Vivo Cytochrome P450 3A (CYP3A) Activity on Etoricoxib Pharmacokinetics and of Etoricoxib Administration on CYP3A Activity
J. Clin. Pharmacol., October 1, 2004; 44(10): 1125 - 1131.
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Drug Metab. Dispos.Home page
T. B. Andersson, E. Bredberg, H. Ericsson, and H. Sjoberg
AN EVALUATION OF THE IN VITRO METABOLISM DATA FOR PREDICTING THE CLEARANCE AND DRUG-DRUG INTERACTION POTENTIAL OF CYP2C9 SUBSTRATES
Drug Metab. Dispos., July 1, 2004; 32(7): 715 - 721.
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Drug Metab. Dispos.Home page
X. Cai, R. W. Wang, R. W. Edom, D. C. Evans, M. Shou, A. D. Rodrigues, W. Liu, D. C. Dean, and T. A. Baillie
VALIDATION OF (-)-N-3-BENZYL-PHENOBARBITAL AS A SELECTIVE INHIBITOR OF CYP2C19 IN HUMAN LIVER MICROSOMES
Drug Metab. Dispos., June 1, 2004; 32(6): 584 - 586.
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Drug Metab. Dispos.Home page
C. Sridar, T. C. Goosen, U. M. Kent, J. A. Williams, and P. F. Hollenberg
SILYBIN INACTIVATES CYTOCHROMES P450 3A4 AND 2C9 AND INHIBITS MAJOR HEPATIC GLUCURONOSYLTRANSFERASES
Drug Metab. Dispos., June 1, 2004; 32(6): 587 - 594.
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Drug Metab. Dispos.Home page
R. L. Walsky and R. S. Obach
VALIDATED ASSAYS FOR HUMAN CYTOCHROME P450 ACTIVITIES
Drug Metab. Dispos., June 1, 2004; 32(6): 647 - 660.
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Mol. Interv.Home page
R. F. Frye
Probing the World of Cytochrome P450 Enzymes
Mol. Interv., June 1, 2004; 4(3): 157 - 162.
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J Clin PharmacolHome page
S.-M. Huang and L. J. Lesko
Drug-Drug, Drug-Dietary Supplement, and Drug-Citrus Fruit and Other Food Interactions: What Have We Learned?
J. Clin. Pharmacol., June 1, 2004; 44(6): 559 - 569.
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Drug Metab. Dispos.Home page
D. M. Stresser, M. I. Broudy, T. Ho, C. E. Cargill, A. P. Blanchard, R. Sharma, A. A. Dandeneau, J. J. Goodwin, S. D. Turner, J. C. L. Erve, et al.
HIGHLY SELECTIVE INHIBITION OF HUMAN CYP3A IN VITRO BY AZAMULIN AND EVIDENCE THAT INHIBITION IS IRREVERSIBLE
Drug Metab. Dispos., January 1, 2004; 32(1): 105 - 112.
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W. Geng
A METHOD FOR IDENTIFICATION OF INHIBITION MECHANISM AND ESTIMATION OF KI IN IN VITRO ENZYME INHIBITION STUDY
Drug Metab. Dispos., November 1, 2003; 31(11): 1456 - 1457.
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K. Ito, D. Hallifax, R. S. Obach, and J. B. Houston
IMPACT OF PARALLEL PATHWAYS OF DRUG ELIMINATION AND MULTIPLE CYTOCHROME P450 INVOLVEMENT ON DRUG-DRUG INTERACTIONS: CYP2D6 PARADIGM
Drug Metab. Dispos., June 1, 2005; 33(6): 837 - 844.
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