Abstract C63: Effects of rolapitant on the pharmacokinetics of digoxin and sulfasalazine in healthy subjects
Authors: Wang Xiaodong , Zhang Zhi-Yi , Arora Sujata , Hughes Lorraine , Wang Jing , Lu Sharon , Christensen Jennifer , Kansra Vikram 
Published: May 2016

Introduction: Rolapitant is a selective and long acting NK-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting (CINV). In vitro results indicated that rolapitant inhibited P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), the efflux transporters that play important roles in drug disposition and distribution, with an IC50 of 7.4 μM and 4.6 μM, respectively. The major metabolite SCH720881 did not inhibit these transporters.

The aims of these studies were to 1) evaluate the effects of rolapitant on the pharmacokinetics (PK) and pharmacodynamics (PD) of a P-gp substrate (digoxin), and on the PK of a BCRP substrate (sulfasalazine); and 2) evaluate the safety and tolerability of rolapitant co-administered with these substrates in healthy subjects.

Methods: These were open-label, drug-drug interaction studies of orally administered substrate (0.5 mg of digoxin or 500 mg sulfasalazine, respectively) in the absence and presence of a single oral dose of 180 mg rolapitant. Cohorts consisted of 16 and 20 subjects, respectively.

For the P-gp study, blood samples for digoxin PK were collected up to 96 hours post digoxin dose in both Period 1 (digoxin alone) and Period 2 (digoxin + a single dose of rolapitant). For PD evaluation, ECGs were performed at specified time points for both Periods 1 and 2. For the BCRP study, blood samples were collected up to 30 hours after Day 1 (sulfasalazine alone), Day 3 (sulfasalazine + rolapitant) and Day 10 (sulfasalazine alone) dosing. All samples were used to evaluate the impact of rolapitant and its major metabolite, SCH720881, on the PK of the relevant substrates.

Results: Co-administration of digoxin with rolapitant increased mean digoxin Cmax value by 71% and mean AUC by 30%; trough concentrations were not impacted. There is no consistent pattern or trend to indicate a different PD profile of digoxin when administered with rolapitant. Digoxin administered either alone or in the presence of rolapitant was well tolerated.

Rolapitant inhibited BCRP resulting in an increase in exposure of sulfasalazine. Geometric mean ratios were 2.4 and 1.2 for Cmax; 2.3 and 1.3 for AUC for the comparison of Day3/Day1 and Day10/Day1, respectively. There were no noteworthy adverse events or laboratory findings in this study.

Conclusions: Rolapitant was well tolerated when co-administered with either the P-gp or BCRP substrate. Co-administration of rolapitant (180 mg) and digoxin (0.5 mg) had no clinically meaningful effect on PD response when compared with digoxin alone. Co-administration of rolapitant (180 mg) increased the exposure of sulfasalazine (500 mg) by approximately 2-fold. Monitoring for adverse reactions related to P-gp or BCRP substrates with a narrow therapeutic index may be necessary if rolapitant is concomitantly administered.

Citation Format: Xiaodong Wang, Zhi-Yi Zhang, Sujata Arora, Lorraine Hughes, Jing Wang, Sharon Lu, Jennifer Christensen, Vikram Kansra. Effects of rolapitant on the pharmacokinetics of digoxin and sulfasalazine in healthy subjects. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C63.