Open AccessEvaluation of Drug–Drug Interactions of Rucaparib and CYP 1A2, CYP 2C9, CYP 2C19, CYP 3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor
Author(s) -
Xiao Jim J.,
Nowak Dorota,
Ramlau Rodryg,
TomaszewskaKiecana Monika,
Wysocki Piotr J.,
Isaacson Jeff,
Beltman Jeri,
Nash Eileen,
Kaczanowski Robert,
Arold Gerhard,
Watkins Simon
Publication year - 2019
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12600
Subject(s) - pharmacology , pharmacokinetics , cyp1a2 , chemistry , cyp2c19 , cyp2c9 , cyp3a , omeprazole , fexofenadine , midazolam , cytochrome p450 , medicine , biochemistry , metabolism , sedation
This phase I study ( CO ‐338‐044; NCT 02740712), conducted in patients with advanced solid tumors, evaluated the effect of the poly( ADP ‐ribose) polymerase (PARP) inhibitor rucaparib on the pharmacokinetics (PK) of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 ( CYP ) 1A2, CYP 2C9, CYP 2C19, and CYP 3A substrates; dosed as a cocktail) and digoxin 0.25 mg (P‐glycoprotein (P‐gp) substrate; dosed separately) without rucaparib and following oral rucaparib 600 mg b.i.d. Geometric mean ( GM ) ratios (90% confidence interval ( CI )) of area under the concentration‐time curve ( AUC ) from time zero to last quantifiable measurement with and without rucaparib were: caffeine, 2.26 (1.93–2.65); S‐warfarin, 1.49 (1.40–1.58); omeprazole, 1.55 (1.32–1.83); midazolam, 1.39 (1.14–1.68); and digoxin, 1.20 (1.12–1.29). There was limited effect on peak concentration of the substrates ( GM ratios, 0.99–1.13). At steady state, rucaparib 600 mg b.i.d. moderately inhibited CYP 1A2, weakly inhibited CYP 2C9, CYP 2C19, and CYP 3A, and marginally increased digoxin exposure.