2016
DOI: 10.1002/cpdd.265
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Compelling Relationship of CYP3A Induction to Levels of the Putative Biomarker 4β‐Hydroxycholesterol and Changes in Midazolam Exposure

Abstract: Having reliable clinical CYP3A biomarkers is attractive to those engaged in drug development as well as to academic groups studying clinical variability resulting from differences or changes in basal individual metabolic status (eg, due to disease or genetics) or drug-drug interactions (DDI). Moreover, if biomarkers can be adequately qualified, it raises the possibility of their use to better anticipate the need, or lack thereof, for defined clinical studies to establish DDI potential. But qualification requir… Show more

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Cited by 8 publications
(6 citation statements)
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“…The CYP3A activity biomarkers, plasma 4bHC and urinary 6bCR, were included as exploratory tools to further our understanding on what changes to expect in the presence of a strong inhibitor/inducer. The 3.6-fold increase in plasma 4bHC by rifampicin after 14 days of dosing in our study is consistent with the model-predicted increases for a strong CYP3A inducer, as described in an earlier publication (Mangold et al, 2016). Based on the biomarker measurement, minimal to no effect of single dose of sonidegib on CYP3A4 activity was observed.…”
Section: Discussionsupporting
confidence: 92%
“…The CYP3A activity biomarkers, plasma 4bHC and urinary 6bCR, were included as exploratory tools to further our understanding on what changes to expect in the presence of a strong inhibitor/inducer. The 3.6-fold increase in plasma 4bHC by rifampicin after 14 days of dosing in our study is consistent with the model-predicted increases for a strong CYP3A inducer, as described in an earlier publication (Mangold et al, 2016). Based on the biomarker measurement, minimal to no effect of single dose of sonidegib on CYP3A4 activity was observed.…”
Section: Discussionsupporting
confidence: 92%
“…The net effect was an increase in observed 4bHC, suggesting CYP3A4 induction. Based on the relationships among midazolam AUC GMR, rifampicin dose, and plasma 4bHC level, a framework has been developed recently to classify the CYP3A4 inducer potencies of new chemical entities after 14 days of dosing (Mangold et al, 2016). Using this framework (although not accepted currently by regulatory authorities) and considering the observed increase in plasma 4bHC in our study (maximal 2-fold increase), midostaurin (100 mg twice daily for 28 days) could be viewed as a moderate CYP3A4 inducer in the worst-case scenario.…”
Section: Pbpk Modeling For Midostaurin-cyp3a4 Interactionmentioning
confidence: 99%
“…The increase in mean 4‐β‐OH‐cholesterol level was observed after repeated dosing of JNJ‐56136379 and confirmed the potential for CYP3A4 induction, as has been observed in nonclinical experiments. 10 , 11 The changes in exposure to midazolam appeared to be more consistent, confirming its value as an exogenous marker of CYP3A4 induction.…”
Section: Discussionmentioning
confidence: 66%