Comparison of Endogenous 4<i>β</i>-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin

Björkhem‐Bergman, Linda; Bäckström, Tobias; Nylén, Hanna; Rönquist-Nii, Yuko; Bredberg, Eva; Andersson, Tommy; Bertilsson, Leif; Diczfalusy, Ulf

doi:10.1124/dmd.113.052316

Cited by 73 publications

(106 citation statements)

References 27 publications

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“…CYP3A4/5 also catalyzes the formation of 4βHC, which is formed from cholesterol [21]. Recent studies suggest that both 6βCR and 4βHC are viable and sensitive biomarkers for CYP3A4 activity; both showed good correlation with changes of the exogenous sensitive probe substrate midazolam when it was coadministered with rifampicin or ketoconazole [12, 14]. …”

Section: Discussionmentioning

confidence: 99%

Comparison of two endogenous biomarkers of CYP3A4 activity in a drug–drug interaction study between midostaurin and rifampicin

Dutreix

Lorenzo

Wang

2014

Eur J Clin Pharmacol

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PurposeMidostaurin, a multitargeted tyrosine kinase inhibitor, is primarily metabolized by CYP3A4. This midostaurin drug–drug interaction study assessed the dynamic response and clinical usefulness of urinary 6β-hydroxycortisol to cortisol ratio (6βCR) and plasma 4β-hydroxycholesterol (4βHC) for monitoring CYP3A4 activity in the presence or absence of rifampicin, a strong CYP3A4 inducer.MethodsForty healthy adults were randomized into groups for either placebo or treatment with rifampicin 600 mg QD for 14 days. All participants received midostaurin 50 mg on day 9. Midostaurin plasma pharmacokinetic parameters were assessed. Urinary 6βCR and plasma 4βHC levels were measured on days 1, 9, 11, and 15.ResultsBoth markers remained stable over time in the control group and increased significantly in the rifampicin group. In the rifampicin group, the median increases (vs day 1) on days 9, 11, and 15 were 4.1-, 5.2-, and 4.7-fold, respectively, for 6βCR and 3.4-, 4.1-, and 4.7-fold, respectively, for 4βHC. Inter- and intrasubject variabilities in the control group were 45.6 % and 30.5 %, respectively, for 6βCR, and 33.8 % and 7.5 %, respectively, for 4βHC. Baseline midostaurin area under the concentration–time curve (AUC) correlated with 4βHC levels (ρ = −0.72; P = .003), but not with 6βCR (ρ = 0.0925; P = .6981).ConclusionsBoth 6βCR and 4βHC levels showed a good dynamic response range upon strong CYP3A4 induction with rifampicin. Because of lower inter- and intrasubject variability, 4βHC appeared more reliable and better predictive of CYP3A4 activity compared with 6βCR. The data from our study further support the clinical utility of these biomarkers.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-014-1675-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Comparison of two endogenous biomarkers of CYP3A4 activity in a drug–drug interaction study between midostaurin and rifampicin

Dutreix

Lorenzo

Wang

2014

Eur J Clin Pharmacol

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“…22 Therefore, rifampicin 10-, 20-, and 100-mg once-daily doses were used to represent weak, moderate, and strong inductions, respectively. Rifampicin 10-, 20-, and 100-mg once-daily doses for 14 days result in 2.0-, 2.6-, and 4.0-fold increases in midazolam clearance, respectively, which correspond to 50%, 62%, and 75% reductions in midazolam systemic exposure (AUC), indicating that it is reasonable to use these rifampicin doses to represent different in vivo induction potencies.…”

Section: Simulations: the Effect Of Weak To Strong Induction Potency mentioning

confidence: 99%

An Exposure‐Response Modeling Approach to Examine the Relationship Between Potency of CYP3A Inducer and Plasma 4β‐Hydroxycholesterol in Healthy Subjects

Jiang¹,

Dutreix

Jarugula³

et al. 2016

Clinical Pharm in Drug Dev

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The objectives of this analysis were to establish the exposure-response relationship between plasma rifampicin and 4β-hydroxycholesterol (4βHC) concentration and to estimate the effect of weak, moderate, and potent CYP3A induction. Plasma rifampicin and 4βHC concentration-time data from a drug-drug interaction study with rifampicin 600 mg were used for model development. An indirect response model with an effect compartment described the relationship between rifampicin and 4βHC concentrations. The model predicted that the equilibration t and 4βHC t were 72.8 and 142 hours, respectively. EM and E of rifampicin induction were 32.6 μg and 8.39-fold, respectively. The population PK-PD model was then used to simulate the effects of rifampicin 10, 20, and 100 mg on plasma 4βHC for up to 21 days, in which rifampicin 10, 20, and 100 mg were used to represent weak, moderate, and strong inducers, respectively. The model-predicted median (5th, 95th percentiles) 1.13 (1.04, 1.44)-, 1.28 (1.10, 1.71)-, and 2.10 (1.45, 3.49)-fold increases in plasma 4βHC after 14-day treatment with rifampicin 10, 20, and 100 mg, respectively. A new drug candidate can likely be classified as a weak, moderate, or strong inducer if baseline-normalized plasma 4βHC increases by <1.13-, 1.13- to 2.10-, or >2.10-fold, respectively, after 14 days of dosing.

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“…The authors state that the ratio "…might be used as a marker to evaluate CYP3A activity at baseline and not only during induction" (Björkhem-Bergman et al, 2013). Although correlation coefficients (r) and/or r 2 values are commonly reported in the literature and used to assume suitability of a cytochrome P450 (P450) probe (Fuhr et al, 2007), r and r 2 values provide limited information.…”

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confidence: 99%

“…A P450 probe should adhere to validation criteria to be considered appropriate for use (Watkins, 1994;Zaigler et al, 2000;Fuhr et al, 2007). Given the limitations of r and r 2 values in general, as well as in these studies (Diczfalusy et al, 2008;Björkhem-Bergman et al, 2013), we do not believe that the 4b-hydroxycholesterol-to-cholesterol ratio has been validated as a biomarker for the measurement of CYP3A activity. …”

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confidence: 99%

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Endogenous 4β-Hydroxycholesterol-to-Cholesterol Ratio Is Not a Validated Biomarker for the Assessment of CYP3A Activity

Joseph

Nafziger²,

Bertino³

2013

Drug Metab Dispos

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Björkhem-Bergman et al. (2013) published a study in healthy adults evaluating endogenous 4b-hydroxycholesterol-to-cholesterol ratio to measure CYP3A induction. The authors compare CYP3A induction fold-changes and determined correlations between 4b-hydroxycholesterolto-cholesterol ratio and midazolam clearance after rifampicin administration. Midazolam clearance is a validated biomarker to evaluate CYP3A activity. We commend the authors for attempting to find alternative, simple, and cost-effective methods to evaluate CYP3A activity. However, we are concerned that the study results may lead to inappropriate use of the 4b-hydroxycholesterol-to-cholesterol ratio for evaluating CYP3A-mediated drug-drug interactions.A statistically significant, but weak, relationship was reported between 4b-hydroxycholesterol-to-cholesterol ratio and midazolam clearance (coefficient of determination [r 2 ] = 0.29, P , 0.01). The authors state that the ratio "…might be used as a marker to evaluate CYP3A activity at baseline and not only during induction" (Björkhem-Bergman et al., 2013). Although correlation coefficients (r) and/or r 2 values are commonly reported in the literature and used to assume suitability of a cytochrome P450 (P450) probe (Fuhr et al., 2007), r and r 2 values provide limited information. Correlation coefficients describe the strength and direction of an association between independent and dependent variables. Coefficients of determination describe the degree of variability between variables. Most importantly, r and r 2 values are not a measure of predictive performance (Sheiner and Beal, 1981;Bland and Altman, 1986). Additional limitations of r 2 values include the inability to determine if the most appropriate set of independent variables was selected, whether independent variables are causes of changes in the dependent variable, and whether omittedvariable bias exists (Nagelkerke, 1991;Draper and Smith, 1998).Additionally, in a previously published study, the authors compared 4b-hydroxycholesterol to another validated CYP3A probe, quinine, and reported weak r values with statistical significance (r = -0.24 to -0.5, P , 0.05) (Diczfalusy et al., 2008). However, statistically significant r and/or r 2 values do not substantiate that a P450 probe is valid for general use. Correlation coefficients and/or coefficients of determination are often overvalued and result in exaggerated conclusions. A P450 probe should adhere to validation criteria to be considered appropriate for use (Watkins, 1994;Zaigler et al., 2000;Fuhr et al., 2007). Given the limitations of r and r 2 values in general, as well as in these studies (Diczfalusy et al., 2008;Björkhem-Bergman et al., 2013), we do not believe that the 4b-hydroxycholesterol-to-cholesterol ratio has been validated as a biomarker for the measurement of CYP3A activity.

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Comparison of Endogenous 4β-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin

Cited by 73 publications

References 27 publications

Comparison of two endogenous biomarkers of CYP3A4 activity in a drug–drug interaction study between midostaurin and rifampicin

Comparison of two endogenous biomarkers of CYP3A4 activity in a drug–drug interaction study between midostaurin and rifampicin

An Exposure‐Response Modeling Approach to Examine the Relationship Between Potency of CYP3A Inducer and Plasma 4β‐Hydroxycholesterol in Healthy Subjects

Endogenous 4β-Hydroxycholesterol-to-Cholesterol Ratio Is Not a Validated Biomarker for the Assessment of CYP3A Activity

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