Gefapixant Does Not Have Meaningful Drug Interactions With A Mate1/2k Inhibitor Or An Oatp1b Substrate

Gefapixant (MK-7264) is a P2X3 receptor antagonist in development for refractory or unexplained chronic cough. In vitro, gefapixant is a substrate of the renal efflux transporters MATE1 and -2K and an inhibitor of the hepatic uptake transporter OATP1B. The potential for gefapixant drug-drug interactions (DDI) was assessed using the probe compounds, pyrimethamine (PYR, a MATE inhibitor) and pitavastatin (PITA, an OATP1B substrate). Two Phase 1 open-label fixed-sequence trials were conducted to assess the single-dose pharmacokinetics (PK) of gefapixant and PITA, respectively. In Trial 1, 12 participants received 45 mg gefapixant alone in Period 1 and, in Period 2, received gefapixant three hours after a single dose of 50 mg PYR. In Trial 2, 20 participants received 1 mg PITA alone in Period 1 and, in Period 2, received 45 mg gefapixant for 4 days; PITA was coadministered with the third dose of gefapixant. Intensive PK samples, including urine in Trial 1, were collected after each dose of the respective victim drugs. Gefapixant and PITA PK (geometric mean ratios [GMR]) are summarized as follows.\n Coadministration of PYR and gefapixant resulted in clinically insignificant increases in gefapixant, attributable to reduced renal clearance. Gefapixant coadministration did not affect PITA exposure. These trials indicate that gefapixant has minimal potential for clinical DDI involving the interrogated transporters.