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Abstract
Midostaurin, 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 6[beta]-hydroxycortisol to cortisol ratio (6[beta]CR) and plasma 4[beta]-hydroxycholesterol (4[beta]HC) for monitoring CYP3A4 activity in the presence or absence of rifampicin, a strong CYP3A4 inducer.
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 day 9. Midostaurin plasma pharmacokinetic parameters were assessed. Urinary 6[beta]CR and plasma 4[beta]HC levels were measured on days 1, 9, 11, and 15.
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 6[beta]CR and 3.4-, 4.1-, and 4.7-fold, respectively, for 4[beta]HC. Inter- and intrasubject variabilities in the control group were 45.6 % and 30.5 %, respectively, for 6[beta]CR, and 33.8 % and 7.5 %, respectively, for 4[beta]HC. Baseline midostaurin area under the concentration-time curve (AUC) correlated with 4[beta]HC levels ([rho]=-0.72; P=.003), but not with 6[beta]CR ([rho]=0.0925; P=.6981).
Both 6[beta]CR and 4[beta]HC levels showed a good dynamic response range upon strong CYP3A4 induction with rifampicin. Because of lower inter- and intrasubject variability, 4[beta]HC appeared more reliable and better predictive of CYP3A4 activity compared with 6[beta]CR. The data from our study further support the clinical utility of these biomarkers.[PUBLICATION ABSTRACT]