Abstract
Riociguat is approved for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Some patients have difficulty swallowing tablets; therefore, 2 randomized, nonblinded, crossover studies compared the relative bioavailability of riociguat oral suspensions and immediate-release (IR) tablet and of crushed-tablet preparations versus whole IR tablet. In study 1, 30 healthy subjects received 5 single riociguat doses: 0.3 and 2.4 mg (0.15 mg/mL suspensions), 0.15 mg (0.03 mg/mL), and 1.0 mg (whole IR tablet) under fasted conditions and 2.4 mg (0.15 mg/mL) after a high-fat, high-calorie American-style breakfast. In study 2, 25 healthy men received 4 single 2.5-mg doses: whole IR tablet and crushed IR tablet suspended in applesauce and water, respectively, under fasted conditions, and whole IR tablet after a continental breakfast. In study 1, dose-normalized pharmacokinetics of riociguat oral suspensions and 1.0-mg whole IR tablet were similar in fasted conditions; 90% confidence intervals for riociguat area under the curve (AUC) to dose and mean maximum concentration (C max) to dose were within bioequivalence criteria. After food, dose-normalized AUC and C max decreased by 15% and 38%, respectively. In study 2, riociguat exposure was similar for all preparations; AUC ratios for crushed-IR-tablet preparations to whole IR tablet were within bioequivalence criteria. The C max increased by 17% for crushed IR tablet in water versus whole IR tablet. Food intake decreased C max of the whole tablet by 16%, with unaltered AUC versus fasted conditions. Riociguat bioavailability was similar between the oral suspensions and the whole IR tablet; exposure was similar between whole IR tablet and crushed-IR-tablet preparations. Minor food effects were observed. Results suggest that riociguat formulations are interchangeable.
Highlights
Riociguat is the first oral, soluble guanylate cyclase stimulator licensed for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension [1-3]
In Study 2, 25 healthy male volunteers received four single doses of riociguat 2.5 mg in a randomised order: oral immediate release” (IR) tablet with water and crushed tablet suspended in applesauce or crushed tablet suspended in water, and oral whole IR tablet after a continental breakfast
In Study 1, dose-normalised pharmacokinetic parameters of riociguat suspensions were almost identical to the standard 1.0 mg IR tablet in fasted conditions (Table 1); 90% confidence intervals for the ratio ‘suspension/IR tablet’ area under concentration (AUC) versus time curve and maximum drug concentration in plasma (Cmax) of riociguat were within the bioequivalence reference range (80–125%)
Summary
Riociguat is the first oral, soluble guanylate cyclase stimulator licensed for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension [1-3]. For some patients with PAH, e.g. children and the elderly, swallowing tablets may be inappropriate or difficult; oral suspension and crushed tablet formulations of riociguat were developed. We present data from two single-centre, randomised, non-blinded, crossover studies evaluating the relative bioavailability of riociguat as oral liquid and standard “immediate release” (IR) oral tablet under fed and fasted conditions, and as a crushed-tablet preparation versus oral tablet under fasted conditions
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