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

Abstract

Purpose: 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 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.

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 day 9. Midostaurin plasma pharmacokinetic parameters were assessed. Urinary 6βCR and plasma 4βHC 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 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).

Conclusions: Both 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.

Fig. 1

Study design. QD once daily, PK pharmacokinetic

Fig. 2

Plasma 4βHC levels and 6βCR over time in both the control (midostaurin + placebo) and treatment (midostaurin + rifampicin) groups (arithmetic mean ± SD). 4βHC 4β-hydroxycholesterol, 6βCR 6β-hydroxycortisol to cortisol ratio

Fig. 3

Correlation between midostaurin AUC_inf and 4βHC levels or 6βCR (day 9) in the placebo control group (upper panel) and in the placebo control plus rifampicin treatment groups combined (lower panel). 4βHC 4β-hydroxycholesterol, 6βCR 6β-hydroxycortisol to cortisol ratio, AUC _inf area under the concentration–time curve from time zero to infinity