129 A phase 1 drug-drug interaction study of CTX-4430 assessing CYP3A4 induction

Abstract

Objectives CTX-4430 is a new anti-inflammatory drug under development for treatment of CF. It is an inhibitor of Leukotriene A4 Hydrolase, the enzyme responsible for production of Leukotriene B4. Because new CF therapies are likely to be administered on top of current standard of care, it is important to assess drug-drug interaction potential early in development. Many important CF drugs comprising current standard of care or nearing approval are substrates for metabolism by CYP3A4. Therefore, we conducted a definitive clinical study in 20 healthy volunteers to assess the potential for CTX-4430 to induce CYP3A4 (NCT02233244). Methods Midazolam is a sensitive substrate for CYP3A4 and is commonly used as a probe for CYP3A4 induction. Prior to administration of CTX-4430, an initial oral dose of midazolam was administered and the PK profiles of midazolam and its primary CYP3A4 metabolite (1-OH-midazolam) were determined. A 100 mg dose of CTX-4430 was then administered orally once daily as a capsule for 7 days. Trough plasma concentrations of CTX-4430 were taken each day to examine its approach to steady state. A second oral dose of midazolam was administered on day 8 and the PK profiles of midazolam and 1-OH-midazolam were determined again. Analyses were carried out to confirm steady state and to compare the PK profiles of midazolam and 1-OH-midazolam before and after CTX-4430 administration. Results CTX-4430 reached steady state over 7 days of once-daily dosing and did not induce CYP3A4. Conclusion These data support continued clinical development of once-daily oral CTX-4430 at a dose of 100 mg.