Drug-drug interaction study between zamicastat and sildenafil in healthy subjects

Zamicastat is a reversible dopamine β-hydroxylase inhibitor that modulate sympathetic nervous system by reducing noradrenaline biosynthesis in peripheral sympathetic nerves. It is currently being developed BIAL - Portela & Ca, S.A. for the treatment of Pulmonary Arterial Hypertension (PAH). As sildenafil may be concomitantly administered with zamicastat in PAH treatment, the potential for drug-drug interactions was investigated. This was an open-label, three period, fixed sequence study in 20 healthy subjects to assess the effect of single dose (SD) of zamicastat on the steady-state pharmacokinetics (PK) of sildenafil and the effect of sildenafil on the PK of zamicastat under fasting conditions, as follows: first period, SD of zamicastat 400 mg, second period, sildenafil 20mg t.i.d from Day 1 to Day 5 and a SD on Day 6; third period, sildenafil 20 mg t.i.d from Day 1 to Day 5, and on Day 6 a concomitant SD of zamicastat 400 mg and sildenafil 20 mg. 90%-confidence intervals (90%CIs) for the geometric mean ratio (GMR) of Cmax, AUC0-t and AUC0-τ,ss of zamicastat and sildenafil were calculated for the comparison between alone vs. concomitant administration. The GMR (90% CI) for Cmax and AUC0-t of zamicastat were 101% (85-119%) and 94% (79-111%), respectively. The GMR (90%CI) for Cmax,ss and AUC0-τ,ss of sildenafil were 100% (84-118%) and 98% (89-107%), respectively. Co-administration of single-dose of zamicastat and sildenafil under steady-state did not significantly affect the peak and total exposure of either drugs. Zamicastat was safe and well tolerated when administered alone and concomitantly with sildenafil.