AN INTEGRATED ASSESSMENT OF PHARMACOKINETICS AND PHARMACODYNAMICS OF ZAMICASTAT: A DOPAMINE Β-HYDROXYLASE INHIBITOR IN HEALTHY VOLUNTEERS
نویسندگان
چکیده
TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: To study (i) the pharmacokinetics (PK) and pharmacodynamics (PD) of Zamicastat its main metabolites (ii) intrinsic extrinsic effects on PK PD profiles. METHODS: Data pooled from six phase-I clinical studies in healthy volunteers (N=366) ≥18 years old both genders were integrated, where oral doses ranging 5 to 2400 mg 1200 mg, administered as a single dose (SD) multiple once-daily (QD), respectively. RESULTS: presented fast moderate absorption, with time peak concentration (tmax) 1.5 6.0 hours 2.0 5.0 post SD repeated QD administration, respectively, no apparent effect. was well distributed an volume distribution between 1429 - 8185 L, following SD. The major route excretion faeces (69.5%) followed by urine (14.2%). mean terminal half-life (t1/2) ranged 11.5-22.6 8.0-17.7 hours, after Plasma exposure higher than accumulation ratios for area under curve (AUC) 3.5. Overall, dose-PK relationship linear plasma (Cmax) AUC across 25 400 dosing modalities. Steady-state reached Days 3 5, clear Two N-dealkylation (BIA 5-453) N-acetylated 5-961) quantified tmax values similar parent. Following administration Zamicastat, increased increments. micronization API 88.5%-98.8% up mg. Food showed positive effect Cmax (77%-307%) (84%-147%), particularly ≥ 200 QD. inhibition DβH activity found be dose-dependent maximum (Emax) 9.2%-62.3% 9.7%-51.5% (tEmax) 2-5 3.5-7 dosing, tested dose. CONCLUSIONS: 400mg. API, food age increase Zamicastat. inhibited manner. CLINICAL IMPLICATIONS: currently development treatment Arterial Hypertension, is reversible dopamine β-hydroxylase (DβH) inhibitor that reduces drive peripheral sympathetic nervous system reducing noradrenaline biosynthesis. DISCLOSURES: No relevant relationships Amílcar Falcão, source=Web Response Employee Bial-Portela & Cª S.A. Please note: >$100000 Helena Gama, Response, value=Salary BIAL-Portela Cª, $1001 $5000 Luis Magalhaes, 2500 4000 Added 04/29/2021 Paulo Magalhães, BIAL 2001-2021 05/07/2021 Nuno Palma, Jose-Francisco Rocha, Amir Ronaghinia, Ana Santos, Board Member Portela Patricio Soares-da-Silva, value=Honoraria
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ژورنال
عنوان ژورنال: Chest
سال: 2021
ISSN: ['0012-3692', '1931-3543']
DOI: https://doi.org/10.1016/j.chest.2021.07.2010