Phase 1 drug-drug interaction study to assess the effect of CYP3A4 inhibition and pan-CYP induction on the pharmacokinetics and safety of fosmanogepix in healthy participants

ABSTRACT Immunocompromised patients are susceptible to fungal infections, and drug-drug interactions with antifungals may occur due to concomitant medications. Fosmanogepix FMGX; active moiety manogepix (MGX) targets glycosylphosphatidylinositol-anchored mannoprotein synthesis and maturation, essential for fungal virulence. This phase 1, fixed-sequence study in healthy participants evaluated the effect of strong CYP3A4 inhibitor itraconazole Cohort 1 ( n = 18); FMGX 500 mg intravenous (IV) twice a day (BID )+ itraconazole 200 mg oral once a day (QD) and pan-CYP inducer rifampin Cohort 2 ( n = 18); FMGX 1,000 mg IV BID + rifampin 600 mg oral QD on the pharmacokinetics of FMGX and MGX. In cohort 1, geometric mean (GM) MGX C max , AUC 0-t , and AUC inf were almost similar with and without itraconazole administration. In Cohort 2, GM MGX C max was slightly lower and AUC 0-t and AUC inf were significantly lower after rifampin administration, with the least squares GM ratio associated 90% confidence intervals (CIs) below 80 – 125% (no effect window). No deaths, serious adverse events (SAEs), or FMGX-related withdrawals were reported. In both cohorts, a total of 188 AEs ( n = 30; 186 mild; two moderate) were reported. In all, 37 of 188 AEs ( n = 12) were considered FMGX related (most frequent: headache, nausea, and hot flush). Administration of FMGX alone and with itraconazole or rifampin was safe and well tolerated. A strong CYP3A4 inhibitor had no effect on FMGX or MGX exposure. A strong pan-CYP inducer had no effect on FMGX exposure but demonstrated ~45% decrease in MGX exposure. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT04166669 and with EudraCT as number 2019-003586-17.