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AN INTEGRATED ASSESSMENT OF PHARMACOKINETICS AND PHARMACODYNAMICS OF ZAMICASTAT: A DOPAMINE Β-HYDROXYLASE INHIBITOR IN HEALTHY VOLUNTEERS

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