Comparison of two endogenous biomarkers of CYP3A4 activity in a drug-drug interaction study between midostaurin and rifampicin.
OBJECTIVE
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.
Novartis Pharma AG Basel, Basel, Switzerland.
Catherine
C
Dutreix
Sebastien
S
Lorenzo
Yanfeng
Y
Wang
D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine; D006888:Hydroxycholesterols / Q000097:blood*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
D015415:Biomarkers; D065701:Cytochrome P-450 CYP3A Inducers; D006888:Hydroxycholesterols; D047428:Protein Kinase Inhibitors; C099828:cholest-5-ene-3,4-diol; C001380:6 beta-hydroxycortisol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019311:Staurosporine; C059539:midostaurin; D012293:Rifampin; D006854:Hydrocortisone