PHASE 1 STUDY TO INVESTIGATE THE EFFECT OF P-GLYCOPROTEIN TRANSPORTER INHIBITION MEDIATED BY CARVEDILOL ON THE PHARMACOKINETICS OF ZAMICASTAT

TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: To investigate the carvedilol-mediated P-gp transporter inhibition on pharmacokinetics (PK) of zamicastat and its metabolites, to safety tolerability zamicastat, when administered alone concomitantly with carvedilol. METHODS: Open-label, 2-periods, fixed-sequence study in 41 healthy subjects assess PK single-dose 200 mg, carvedilol under fed conditions. In first treatment period, received a single oral dose mg., second after washout period at least 10 days, daily doses for 6 days (12.5 mg Day 1 2, 25 Days 3 6). On 7, were co-administered. Two-sided 90% confidence intervals (90%CIs) geometric mean ratio (GMR) Cmax, AUC0-t AUC0-inf calculated comparison between test (zamicastat carvedilol) reference alone). RESULTS: The GMR (90% CI) AUC0-t, 110% (100%-121%), (105%-115%), (105%-115%) respectively. Median tmax occurred 4 hours both periods. Co-administration lowered extent exposure minor metabolites BIA 5-453 [AUC0-t 78% (70%-86%)] 5-961 64% (56%-73%)]. rate metabolite was decreased presence [Cmax 79% (74%-85%)].No serious adverse events or (AEs) severe intensity during study. Two withdrew one subject due AE “blood bilirubin increased” assessed as mild not related other consent before intake. CONCLUSIONS: carvedilol, strong inhibitor P-gp, had no substantial effect therefore it is expected that such interaction devoid therapeutic impact. CLINICAL IMPLICATIONS: P-glycoprotein (P-gp) clinically important efflux extensively expressed various tissues including gastrointestinal tract, liver, kidney brain, which has potential impact bioavailability, tissue distribution, hepatic renal elimination substrates. Zamicastat reversible dopamine β-hydroxylase inhibitor, modulate sympathetic nervous system by reducing norepinephrine biosynthesis peripheral nerves, granted Orphan Drug Designation Food Administration Arterial Hypertension. DISCLOSURES: No relevant relationships Guillermo Castilla Fernández, source=Web Response andreia guimaraes, Employee relationship BIAL-Portela & Cª, S.A. Please note: $1001 - $5000 Luis Magalhaes, Response, value=Salary 2500 4000 Added 04/29/2021 Ana Santos, Board Member BIAL Portela Cª >$100000 Patricio Soares-da-Silva, value=Honoraria Bial ongoing 05/06/2021 Mariana Vieira,