Presentation Authors: Matthew P Rutman*, New York, NY, Jennifer R King, Nate Bennett, Durham, NC, Wendy Ankrom, Kenilworth, NJ, Paul N Mudd, Durham, NC
Introduction: Vibegron is a selective Î²3-adrenergic receptor agonist in development for overactive bladder (OAB). Approximately 43% of patients on any OAB medication are taking a drug metabolized through the CYP2D6 pathway. In vitro data (human liver microsomal incubations and hepatocyte cultures) demonstrate that vibegron at concentrations up to 100 Î¼M does not inhibit human cytochrome P450 (CYP) enzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Two clinical studies were conducted to evaluate the pharmacokinetic, safety, and tolerability effects of vibegron on the CYP2D6 substrates tolterodine and metoprolol in healthy volunteers.
Methods: Two phase-1, single-center, open-label studies enrolled healthy volunteers to receive multiple-dose tolterodine extended release (ER) 4 mg with and/or without multiple doses of vibegron 100 mg (n=12), or single-dose metoprolol succinate 100 mg with and without multiple-dose vibegron 75 mg (n=24). Pharmacokinetic parameters were calculated to evaluate tolterodine or metoprolol alone and in combination with steady-state vibegron. Safety and tolerability were assessed throughout the study.
Results: Coadministration of vibegron did not alter the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of tolterodine (geometric mean ratio [90% confidence intervals], 1.12 [1.00, 1.26] and 1.08 [0.97, 1.21]), respectively. The elimination half-life of tolterodine was similar alone and in the presence of steady-state vibegron (9.34 hr alone vs 9.48 hr in combination). Metoprolol geometric mean Cmax and AUC values increased slightly in the presence of vibegron by 49% (1.49 [1.35-1.65]) and 40% (1.40 [1.30-1.52]) respectively. However, the elimination half-life of metoprolol was similar alone and with vibegron (9.49 hr alone vs 10.88 hr in combination), suggesting CYP2D6 was unlikely inhibited. Study treatments were well tolerated, with no evidence of increased rates of adverse events during combination administration with vibegron.
Conclusions: Clinically significant drug-drug interactions (DDI) do not occur when vibegron is administered with tolterodine or metoprolol. In total, the in vitro and clinical data demonstrate that vibegron does not inhibit CYP2D6 and has a favorable DDI profile for use in patients with OAB.
Source of Funding: Funding for these trials were supported by Merck & Co., Inc.