Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension

Figures

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  Figure 1. PK model: compartments (boxes), drug flow (arrows), and model parameters. Absorption, drug flow between central and peripheral compartments, metabolism, and elimination of selexipag and ACT‐333679 are first‐order processes.

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  Figure 2. Population‐typical concentration–time profile of selexipag (left) and ACT‐333679 (right) at steady‐state doses of 1,600 μg b.i.d. with interindividual variation. Colored areas indicate ranges of simulated concentration–time profiles (10th to 20th, …, 80th to 90th percentile as indicated by the color legend on the right‐hand side).

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  Figure 3. Covariate effects: Concentration–time profiles at steady state for selexipag and ACT‐333679 for (a) body weights of 51, 70, and 96 kg, (b) male and female, (c) concomitant PAH medication, and (d) total bilirubin at baseline at steady‐state doses of 1,600 μg b.i.d. Time denotes time after first dose. Some lines overlay since there was no effect of sex and PAH comedication on selexipag. The typical (reference) patient had 70 kg body weight, was female with total bilirubin at baseline of 10 μmol/L, and PAH comedication‐naïve.

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  Figure 4. Comparison of PK models for PAH patients and healthy subjects: Model‐predicted concentration–time profiles of selexipag and ACT‐333679 for a male subject with 80 kg body weight, total bilirubin 13 μmol/L, and no PAH comedication (healthy model) or naïve (patient model) at a steady‐state dose of 1,600 μg b.i.d.