The effect of fluconazole on the pharmacokinetics of ensifentrine in healthy individuals

Ensifentrine (RPL554) is an investigational, dual PDE3/4 inhibitor metabolized by CYP2C9. This study evaluated the urine and plasma pharmacokinetic (PK) effect of CYP2C9 inhibitor, fluconazole, in combination with ensifentrine. This was a phase 1, open-label, three-period study to assess the effect of fluconazole on PK of ensifentrine in 28 healthy subjects. Subjects received single doses of nebulized ensifentrine (3mg) on Day 1 and Day 11 and fluconazole 400mg on Day 4 then 200mg on Days 5-13. Ensifentrine plasma and urine PK sampling performed pre-dose and up to 72 hours post-dose on Days 1 and 11. Safety assessed with 12-lead ECGs, vitals, adverse events, laboratory values and physical examinations. Primary endpoint was measured as maximum plasma concentration of ensifentrine (Cmax) and Area Under the Curve from 0-extrapolated to infinity (AUC0-inf) pre-dose and up to 72 hours post-dose. Study enrolled 29 subjects (17 male, 18 black) with mean age of 32.5 years. Plasma was analyzed in 26 and urine in 29 patients. When dosed concomitantly with fluconazole, ensifentrine Cmax and AUC0-inf were 41% and 63% higher compared to ensifentrine alone. Urinary excretion of ensifentrine was negligible (<0.3%). There were 9 TEAEs, none were serious. Co-administration of fluconazole with ensifentrine was well tolerated and had a minimal effect on Cmax and AUC of less than 2-fold, which is not considered clinically relevant.