The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first‐in‐class ACKR3/CXCR7 antagonist, ACT‐1004‐1239

Abstract Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug–drug interactions (DDIs). ACT‐1004‐1239 is a potent and selective, first‐in‐class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT‐1004‐1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single‐dose ACT‐1004‐1239 in healthy male subjects. In the open‐label, fixed‐sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT‐1004‐1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT‐1004‐1239 in the second period. We report a median of difference in tmax (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of Cmax and AUC0−∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of t1/2 was 1.46 (1.26, 1.70). Both treatments were well‐tolerated with an identical incidence in subjects reporting treatment‐emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT‐1004‐1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2‐ to