Rucaparib and Clopidogrel: Interaction Details

a) Concomitant use of clopidogrel 75 mg and omeprazole 10 mg, a CYP2C19 inhibitor, (administered together in the morning or 12 hours apart in the evening) resulted in a significant reduction in mean inhibition of platelet aggregation compared with clopidogrel alone (47.2% vs 56%) measured 4 hours after the last clopidogrel dose on day 7, in a study of healthy Japanese subjects with different CYP2C19 genotypes (N=41). A similar significant reduction was seen with esomeprazole, lansoprazole, and RABEprazole when given together in the morning or separately in the evening. However, the reduction in inhibition of platelet aggregation was not significant with clopidogrel given after breakfast and RABEprazole administered after lunch (4 hours after or 20 hours prior to clopidogrel) ².

b) In a study of patients with coronary artery disease, the inhibition of platelet aggregation (IPA) of clopidogrel was significantly reduced with the addition of omeprazole, a CYP2C19 inhibitor, (n=41; clopidogrel, 26.3%; combination therapy, 17.4%), but was not significantly changed with the addition of raNITIdine therapy (n=44; 32.6%; combination therapy, 30.1%). All patients received aspirin 100 mg daily prior to and during the study and had a baseline IPA measurement (0% for each group). Patients then received clopidogrel 75 mg daily for one week prior to the second IPA measurement (time 1), then were randomized to receive combination therapy with clopidogrel and either omeprazole 20 mg twice daily or raNITIdine 150 mg twice daily for one week before the next IPA measurement (time 2). There was not a significant difference between groups for either time 1 or time 2. After excluding patients who were homozygous for 2C19*2 (loss-of-function) genotype, there was a significant difference between groups at time 2 ³.

c) Coadministration of clopidogrel and omeprazole, a CYP2C19 inhibitor, led to a significant decrease in Cmax and AUC of clopidogrel active metabolite (H4), and consequently, a decrease in platelet aggregation inhibition in 3, randomized, placebo-controlled, crossover studies in healthy subjects. Compared with levels when clopidogrel was administered alone, coadministration of clopidogrel (300-mg loading dose; 75 mg/day maintenance dose) and omeprazole (80 mg/day; study 1; n=64) led to a 46% and 45% decrease in H4 Cmax and AUC, respectively on day 1, and a 42% and 40% decrease, respectively on day 5. The decrease in H4 Cmax and AUC corresponded to a decrease in mean inhibition of platelet aggregation (IPA) of 39% on day 1. and 21% on day 5. Results were similar when clopidogrel and omeprazole were administered 12 hours apart at the same doses (study 2; n=66), and when clopidogrel loading- and maintenance doses were doubled (study 3; n=62). In a fourth study (n=56), substitution of omeprazole with pantoprazole 80 mg/day coadministered with clopidogrel (300-mg loading dose; 75 mg/day maintenance dose), led to a smaller but still significant decrease in H4 Cmax and AUC of 24% and 20%, respectively on day 1, and 28% and 14%, respectively on day 5 compared with levels when clopidogrel was administered alone ⁴.

d) In a double-blind, placebo-controlled trial of 140 patients undergoing coronary artery stent implantation, omeprazole 20 mg/day, a CYP2C19 inhibitor, significantly decreased clopidogrel inhibitory effect on platelet P2Y12 as assessed by vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay. Clopidogrel exerts its antiplatelet effect by forming an inactivating disulfide bond with the platelet P2Y12 ADP receptor, which is then associated with dephosphorylation of VASP. This dephosphorylation provides an index of platelet reactivity to clopidogrel in which the higher the platelet reactivity index (PRI), the more frequently thrombosis occurs (clopidogrel resistance). Consecutive patients received aspirin 75 mg/day and a loading dose (300 mg) of clopidogrel (followed by 75 mg/day), followed by randomization to either omeprazole or placebo for 7 days. PRI was measured day 1 and 7, and data analyzed for 124 patients. The mean PRI was similar in both groups on day 1, 83.2%) for the placebo group compared with 83.9% for the omeprazole group. On day 7, mean PRI was 39.8% and 51.4%, respectively. Mean PRI variation in the placebo group was -43.3% and -32.6% in the omeprazole group. Sixteen patients (26.7%) in the placebo group were determined to be poor responders to clopidogrel compared with 39 (60.9%) in the omeprazole group (odds ratio, 4.31; 95% confidence interval, 2 to 9.2) ⁵.