Evaluation of Drug-Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp Substrates in Patients With an Advanced Solid Tumor

Jim J Xiao, Dorota Nowak, Rodryg Ramlau, Monika Tomaszewska-Kiecana, Piotr J Wysocki, Jeff Isaacson, Jeri Beltman, Eileen Nash, Robert Kaczanowski, Gerhard Arold, Simon Watkins, Jim J Xiao, Dorota Nowak, Rodryg Ramlau, Monika Tomaszewska-Kiecana, Piotr J Wysocki, Jeff Isaacson, Jeri Beltman, Eileen Nash, Robert Kaczanowski, Gerhard Arold, Simon Watkins

Abstract

This phase I study (CO-338-044; NCT02740712), 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, CYP2C9, CYP2C19, and CYP3A 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 CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and marginally increased digoxin exposure.

© 2018 Clovis Oncology Inc. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Study schema. CYP, cytochrome P450.
Figure 2
Figure 2
Arithmetic mean (SD) plasma concentration‐time profiles for (a) caffeine, (b) S‐warfarin, (c) omeprazole, (d) midazolam, and (e) digoxin administered with (blue line) and without (red line) rucaparib. *Following the caffeine dose on day 1, 9 of the 16 evaluable patients had caffeine concentrations lower than the quantification limit at 72 hours postdose. One subject had a higher than expected concentration at the same time point, presumably due to incidental caffeine intake, contributing to an apparent spike in the mean caffeine pharmacokinetic profile. The presumed incidental caffeine intake in this one patient had no impact on CYP1A2 DDI assessment based on Cmax and AUC 0‐inf. AUC 0‐inf, area under the concentration‐time curve extrapolated from time 0 to infinity; Cmax, peak plasma concentration; DDI, drug–drug interaction.
Figure 3
Figure 3
Effect of rucaparib on the pharmacokinetics of probe drugs. AUC 0‐72 h, area under the concentration‐time curve from time 0−72 hours; AUC 0‐96 h, area under the concentration‐time curve from time 0−96 hours; AUC 0‐inf, area under the concentration‐time curve extrapolated from time 0 to infinity; CI, confidence interval; CYP, cytochrome P450; Cmax, peak plasma concentration; P‐gp, P‐glycoprotein.

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