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Eur J Clin Pharmacol (2014) 70:915920 DOI 10.1007/s00228-014-1675-0
CLINICAL TRIAL
Comparison of two endogenous biomarkers of CYP3A4 activity in a drugdrug interaction study between midostaurinand rifampicin
Catherine Dutreix & Sebastien Lorenzo & Yanfeng Wang
Received: 20 February 2014 /Accepted: 27 March 2014 /Published online: 21 May 2014 # The Author(s) 2014. This article is published with open access at Springerlink.com
AbstractPurpose Midostaurin, a multitargeted tyrosine kinase inhibitor, is primarily metabolized by CYP3A4. This midostaurin drugdrug interaction study assessed the dynamic response and clinical usefulness of urinary 6-hydroxycortisol to cortisol ratio (6CR) and plasma 4-hydroxycholesterol (4HC) for monitoring CYP3A4 activity in the presence or absence of rifampicin, a strong CYP3A4 inducer.
Methods Forty 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 day9. Midostaurin plasma pharmacokinetic parameters were assessed. Urinary 6CR and plasma 4HC levels were measured on days 1, 9, 11, and 15.
Results Both 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 6CR and3.4-, 4.1-, and 4.7-fold, respectively, for 4HC. Inter- and intrasubject variabilities in the control group were 45.6 % and30.5 %, respectively, for 6CR, and 33.8 % and 7.5 %, respectively, for 4HC. Baseline midostaurin area under the concentrationtime curve (AUC) correlated with 4HC levels (=0.72; P=.003), but not with 6CR (=0.0925; P=.6981).
Conclusions Both 6CR and 4HC levels showed a good dynamic response range upon strong CYP3A4 induction with rifampicin. Because of lower inter- and intrasubject variability, 4HC appeared more reliable and better predictive of CYP3A4 activity compared with 6CR. The data from our study further support the clinical utility of these biomarkers.
Keywords Midostaurin . Rifampicin . CYP3A4 biomarker . 4-hydroxycholesterol . 6-hydroxycortisol to cortisol ratio
Introduction
Cytochrome P450 3A4 (CYP3A4), the most abundant human CYP isoform [1], is involved in the metabolism of approximately half of all marketed drugs [2]. However, there is large intersubject variability in the expression and activity of CYP3A4, resulting from both genetic and nongenetic factors [3]. Sensitive probes such as midazolam are often used as exogenous...