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Research ArticlePerspective

Evaluation of CYP2B6 Induction and Prediction of Clinical Drug–Drug Interactions: Considerations from the IQ Consortium Induction Working Group—An Industry Perspective

Odette A. Fahmi, Mohamad Shebley, Jairam Palamanda, Michael W. Sinz, Diane Ramsden, Heidi J. Einolf, Liangfu Chen and Hongbing Wang
Drug Metabolism and Disposition October 2016, 44 (10) 1720-1730; DOI: https://doi.org/10.1124/dmd.116.071076
Odette A. Fahmi
Pfizer Inc., Groton, Connecticut (O.A.F.); AbbVie Inc., North Chicago, Illinois (M.S.); Merck Research Laboratories, Rahway, New Jersey (J.P.); Bristol-Myers Squibb, Wallingford, Connecticut (M.W.S.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); and University of Maryland School of Pharmacy, Baltimore, Maryland (H.W.)
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Mohamad Shebley
Pfizer Inc., Groton, Connecticut (O.A.F.); AbbVie Inc., North Chicago, Illinois (M.S.); Merck Research Laboratories, Rahway, New Jersey (J.P.); Bristol-Myers Squibb, Wallingford, Connecticut (M.W.S.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); and University of Maryland School of Pharmacy, Baltimore, Maryland (H.W.)
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Jairam Palamanda
Pfizer Inc., Groton, Connecticut (O.A.F.); AbbVie Inc., North Chicago, Illinois (M.S.); Merck Research Laboratories, Rahway, New Jersey (J.P.); Bristol-Myers Squibb, Wallingford, Connecticut (M.W.S.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); and University of Maryland School of Pharmacy, Baltimore, Maryland (H.W.)
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Michael W. Sinz
Pfizer Inc., Groton, Connecticut (O.A.F.); AbbVie Inc., North Chicago, Illinois (M.S.); Merck Research Laboratories, Rahway, New Jersey (J.P.); Bristol-Myers Squibb, Wallingford, Connecticut (M.W.S.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); and University of Maryland School of Pharmacy, Baltimore, Maryland (H.W.)
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Diane Ramsden
Pfizer Inc., Groton, Connecticut (O.A.F.); AbbVie Inc., North Chicago, Illinois (M.S.); Merck Research Laboratories, Rahway, New Jersey (J.P.); Bristol-Myers Squibb, Wallingford, Connecticut (M.W.S.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); and University of Maryland School of Pharmacy, Baltimore, Maryland (H.W.)
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Heidi J. Einolf
Pfizer Inc., Groton, Connecticut (O.A.F.); AbbVie Inc., North Chicago, Illinois (M.S.); Merck Research Laboratories, Rahway, New Jersey (J.P.); Bristol-Myers Squibb, Wallingford, Connecticut (M.W.S.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); and University of Maryland School of Pharmacy, Baltimore, Maryland (H.W.)
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Liangfu Chen
Pfizer Inc., Groton, Connecticut (O.A.F.); AbbVie Inc., North Chicago, Illinois (M.S.); Merck Research Laboratories, Rahway, New Jersey (J.P.); Bristol-Myers Squibb, Wallingford, Connecticut (M.W.S.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); and University of Maryland School of Pharmacy, Baltimore, Maryland (H.W.)
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Hongbing Wang
Pfizer Inc., Groton, Connecticut (O.A.F.); AbbVie Inc., North Chicago, Illinois (M.S.); Merck Research Laboratories, Rahway, New Jersey (J.P.); Bristol-Myers Squibb, Wallingford, Connecticut (M.W.S.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); and University of Maryland School of Pharmacy, Baltimore, Maryland (H.W.)
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Abstract

Drug–drug interactions (DDIs) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by regulatory agencies. This work aimed to evaluate the potency of CYP2B6 versus CYP3A4 induction in vitro and from clinical studies and to assess the predictability of efavirenz versus bupropion as clinical probe substrates of CYP2B6 induction. The analysis indicates that the magnitude of CYP3A4 induction was higher than CYP2B6 both in vitro and in vivo. The magnitude of DDIs caused by induction could not be predicted for bupropion with static or dynamic models. On the other hand, the relative induction score, net effect, and physiologically based pharmacokinetics SimCYP models using efavirenz resulted in improved DDI predictions. Although bupropion and efavirenz have been used and are recommended by regulatory agencies as clinical CYP2B6 probe substrates for DDI studies, CYP3A4 contributes to the metabolism of both probes and is induced by all reference CYP2B6 inducers. Therefore, caution must be taken when interpreting clinical induction results because of the lack of selectivity of these probes. Although in vitro–in vivo extrapolation for efavirenz performed better than bupropion, interpretation of the clinical change in exposure is confounded by the coinduction of CYP2B6 and CYP3A4, as well as the increased contribution of CYP3A4 to efavirenz metabolism under induced conditions. Current methods and probe substrates preclude accurate prediction of CYP2B6 induction. Identification of a sensitive and selective clinical substrate for CYP2B6 (fraction metabolized > 0.9) is needed to improve in vitro–in vivo extrapolation for characterizing the potential for CYP2B6-mediated DDIs. Alternative strategies and a framework for evaluating the CYP2B6 induction risk are proposed.

Footnotes

    • Received April 20, 2016.
    • Accepted July 14, 2016.
  • dx.doi.org/10.1124/dmd.116.071076.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (10)
Drug Metabolism and Disposition
Vol. 44, Issue 10
1 Oct 2016
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Research ArticlePerspective

CYP2B6 Induction and Prediction of Clinical DDIs

Odette A. Fahmi, Mohamad Shebley, Jairam Palamanda, Michael W. Sinz, Diane Ramsden, Heidi J. Einolf, Liangfu Chen and Hongbing Wang
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1720-1730; DOI: https://doi.org/10.1124/dmd.116.071076

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Research ArticlePerspective

CYP2B6 Induction and Prediction of Clinical DDIs

Odette A. Fahmi, Mohamad Shebley, Jairam Palamanda, Michael W. Sinz, Diane Ramsden, Heidi J. Einolf, Liangfu Chen and Hongbing Wang
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1720-1730; DOI: https://doi.org/10.1124/dmd.116.071076
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