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Medientyp:
E-Artikel
Titel:
Evaluation of Drug–Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P‐gp Substrates in Patients With an Advanced Solid Tumor
Beteiligte:
Xiao, Jim J.;
Nowak, Dorota;
Ramlau, Rodryg;
Tomaszewska‐Kiecana, Monika;
Wysocki, Piotr J.;
Isaacson, Jeff;
Beltman, Jeri;
Nash, Eileen;
Kaczanowski, Robert;
Arold, Gerhard;
Watkins, Simon
Beschreibung:
<jats:p>This phase I study (<jats:styled-content style="fixed-case">CO</jats:styled-content>‐338‐044; <jats:styled-content style="fixed-case">NCT</jats:styled-content>02740712), conducted in patients with advanced solid tumors, evaluated the effect of the poly(<jats:styled-content style="fixed-case">ADP</jats:styled-content>‐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 (<jats:styled-content style="fixed-case">CYP</jats:styled-content>) 1A2, <jats:styled-content style="fixed-case">CYP</jats:styled-content>2C9, <jats:styled-content style="fixed-case">CYP</jats:styled-content>2C19, and <jats:styled-content style="fixed-case">CYP</jats:styled-content>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 (<jats:styled-content style="fixed-case">GM</jats:styled-content>) ratios (90% confidence interval (<jats:styled-content style="fixed-case">CI</jats:styled-content>)) of area under the concentration‐time curve (<jats:styled-content style="fixed-case">AUC</jats:styled-content>) 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 (<jats:styled-content style="fixed-case">GM</jats:styled-content> ratios, 0.99–1.13). At steady state, rucaparib 600 mg b.i.d. moderately inhibited <jats:styled-content style="fixed-case">CYP</jats:styled-content>1A2, weakly inhibited <jats:styled-content style="fixed-case">CYP</jats:styled-content>2C9, <jats:styled-content style="fixed-case">CYP</jats:styled-content>2C19, and <jats:styled-content style="fixed-case">CYP</jats:styled-content>3A, and marginally increased digoxin exposure.</jats:p>