Mass Balance, Pharmacokinetics, and Metabolism of 14C-labeled ACT-128800 Administered to Healthy Male Subjects

On Day 1, immediately prior to the intake of study drug, subjects were instructed to empty their bladders. Thereafter, following drug intake all urine produced was collected for 10 days up to Day 11 (morning). Following administration of 14C-ACT-128800, urine samples were collected in three consecutive 8-hour intervals, from 0-8 h, 8-16 h, and 16-24 h. From Day 2 to Day 10 (inclusive), urine samples were collected at 24-hour intervals. In case of an extended observation period, urine samples were also collected at 24-hour intervals. The total amount of radioactivity was measured using a liquid scintillation counter.

Between Day -3 and Day -1, a baseline faeces sample was collected in a light-protected polypropylene box from each subject.

From Day 1 (post-dose) to Day 10 (inclusive), all faeces samples and the toilet paper were collected in pre-weighed, light-protected polypropylene boxes. Each faeces sample was collected in a separate box and weighed. The weight of the sample and the time of collection were recorded. All faecal samples were frozen as soon as possible and stored in an upright position at -70 °C or below.The total amount of radioactivity was measured using a liquid scintillation counter.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity. The amount of radioactivity was measured using a liquid scintillation counter. The measured radioactivity was used to directly obtain Cmax.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity. The amount of radioactivity was measured using a liquid scintillation counter. The measured radioactivity was used to directly obtain tmax.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity. The amount of radioactivity was measured using a liquid scintillation counter. AUC(0-t) was calculated according to the linear trapezoidal rule, using the measured concentration-time values above the limit of quantification.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity. The amount of radioactivity was measured using a liquid scintillation counter. AUC(0-infinity) was calculated by combining AUC(0-t) and AUC(extra). AUC(extra) represents an extrapolated value obtained by Ct/λz,, where Ct is the last concentration above the limit of quantification and λz, represents the terminal elimination rate constant determined by log-linear regression analysis of the measured concentrations in the terminal elimination phase.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity. The amount of radioactivity was measured using a liquid scintillation counter. t1/2 was calculated as follows: t1/2 = ln 2/λz, where ln 2 is the natural log of 2 (approximately 0.693).

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity. The amount of radioactivity was measured using a liquid scintillation counter. The measured radioactivity was used to directly obtain Cmax.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity. The amount of radioactivity was measured using a liquid scintillation counter. The measured radioactivity was used to directly obtain tmax.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity. The amount of radioactivity was measured using a liquid scintillation counter. AUC(0-t) was calculated according to the linear trapezoidal rule, using the measured concentration-time values above the limit of quantification.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity. The amount of radioactivity was measured using a liquid scintillation counter. AUC(0-infinity) was calculated by combining AUC(0-t) and AUC(extra). AUC(extra) represents an extrapolated value obtained by Ct/λz,, where Ct is the last concentration above the limit of quantification and λz, represents the terminal elimination rate constant determined by log-linear regression analysis of the measured concentrations in the terminal elimination phase.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.0 mL was used for measurement of radioactivity.The amount of radioactivity was measured using a liquid scintillation counter. t1/2 was calculated as follows: t1/2 = ln 2/λz, where ln 2 is the natural log of 2 (approximately 0.693).

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.7 mL was used for measurement of ACT-12880 concentration. The concentration of ACT-128800 was determined using a validated liquid chromatography-tandem mass spectrometry assay was used to directly obtain Cmax.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.7 mL was used for measurement of ACT-12880 concentration. The concentration of ACT-128800 was determined using a validated liquid chromatography-tandem mass spectrometry assay was used to directly obtain tmax.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.7 mL was used for measurement of ACT-12880 concentration. The concentration of ACT-128800 was determined using a validated liquid chromatography-tandem mass spectrometry assay . AUC(0-t) was calculated according to the linear trapezoidal rule, using the measured concentration-time values above the limit of quantification.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.7 mL was used for measurement of ACT-12880 concentration. The concentration of ACT-128800 was determined using a validated liquid chromatography-tandem mass spectrometry assay . AUC(0-infinity) was calculated by combining AUC(0-t) and AUC(extra). AUC(extra) represents an extrapolated value obtained by Ct/λz,, where Ct is the last concentration above the limit of quantification and λz, represents the terminal elimination rate constant determined by log-linear regression analysis of the measured concentrations in the terminal elimination phase.

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.7 mL was used for measurement of ACT-12880 concentration. The concentration of ACT-128800 was determined using a validated liquid chromatography-tandem mass spectrometry assay . t1/2 was calculated as follows: t1/2 = ln 2/λz, where ln 2 is the natural log of 2 (approximately 0.693).

Blood samples were collected from an antecubital vein by direct venipuncture or via an intravenous catheter at various time points up to the end of study. An aliquot of 2.7 mL was used for measurement of lymphocyte count

Blood pressure was measured at various time points up to the end of study using an automatic oscillometric device. Measurements were taken with the subject in the supine position after a resting period of at least 5 minutes. The leading (writing) arm was used for all blood pressure measurements.

Blood pressure was measured at various time points up to the end of study using an automatic oscillometric device. Measurements were taken with the subject in the supine position after a resting period of at least 5 minutes. The leading (writing) arm was used for all blood pressure measurements.

Heart rate was measured at various time points up to the end of study using an automatic oscillometric device. Measurements were taken with the subject in the supine position after a resting period of at least 5 minutes. The leading (writing) arm was used for all blood pressure measurements.

Body temperature was measured at various time points up to the end of study.

Body weight was measured at baseline and at end of study using the same weighing scales for all subjects. The weighing scales had a precision of at least 0.5 kg.