SUMMARY

• Clinical research designed to investigate the efficacy and/or safety of selexipag in the treatment of pulmonary arterial hypertension (PAH) in patients undergoing renal dialysis has not been performed.
• In the pivotal, phase 3 GRIPHON study investigating the efficacy, safety, and tolerability of UPTRAVI in patients with symptomatic PAH, patients with severe renal insufficiency were excluded from participation.^1,2
• Kaufmann et al (2016)³ reported data from a phase 1 pharmacokinetic study to assess the pharmacokinetics of selexipag in subjects with severe renal impairment (SRI; estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²), compared with healthy subjects. However, subjects with SRI were excluded if they required dialysis. Mean exposures to selexipag and ACT-333679 were increased 1.7-fold and 1.4-fold, respectively, in subjects with SRI compared with healthy subjects. Based on these data, the study authors suggested that no adjustment of the starting dose of selexipag is needed for patients with severe renal function impairment. However, the authors did recommend that up-titration be done with caution in this patient population. Further details of this study are summarized below.
• An additional citation is included in the REFERENCES section for your review.⁴
• Please note that this document does not contain any reference to the local prescribing information. For specific information on the different therapeutic indications and the safety warnings and precautions (including use in patients undergoing dialysis) for UPTRAVI in your country, please refer to your local product information.

CLINICAL DATA

GRIPHON Study

In the pivotal, phase 3 GRIPHON study investigating the efficacy, safety and tolerability of UPTRAVI in patients with symptomatic PAH, patients with severe renal insufficiency were excluded from participation.^1,2

Phase 1 Pharmacokinetic Study

Kaufmann et al (2016)³ reported data from a phase 1 study designed to investigate the pharmacokinetics, tolerability and safety of selexipag and its active metabolite, ACT333679, in subjects with SRI as compared to healthy subjects.

Study design/Methods

• Prospective, single-center, parallel group, open-label, single-dose phase 1 study
• Participants: 8 subjects with SRI (eGFR <30 mL/min/1.73 m²; group A) compared to 8 healthy subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²; group B).
• Subjects with SRI were excluded if they required dialysis, had a hemoglobin concentration 9 g/dL or if they had to follow strict fluid restriction (1000 mL/24 h).
• Selexipag treatment: single dose of 400 mcg

Results

• Selexipag was absorbed with a median (range) time to peak plasma concentrations (t_max) of 2.0 h (1.0-5.0) and 1.5 h (0.5-6) in subjects with SRI and healthy subjects, respectively.
• Exposure to selexipag (both peak plasma concentration [C_max] or area under plasma concentration-time curve from zero to infinity [AUC_0-∞]) was increased 1.7-fold in subjects with SRI compared with healthy subjects (calculated as the between-group ratios of geometric means, with 90% confidence intervals (CIs) of 1.2-2.5 and 1.3-2.3 for the respective parameters).
• Selexipag had a similar terminal elimination half-life (t_1/2) in subjects with SRI (1.4 hours) and healthy subjects (1.0 hours; ratio of geometric means [90% CI]: 0.75 [0.5-1.2]).
• The active metabolite ACT­333679 had a similar median (range) t_max of 4.0 h (1.5-6.0) and 4.5 h (2.0-8.0) in SRI and healthy subjects, respectively.
• Similar to selexipag, C_max and AUC_0-∞ of ACT­333679 were increased 1.4-fold and 1.6- fold, respectively, in subjects with SRI compared with healthy subjects (calculated as the between-group ratios of geometric means, with 90% CIs of 1.0-2.1 and 0.6-4.2 for the respective parameters).
• ACT­333679 had a longer t_1/2 in subjects with SRI (13.4 h) than in healthy subjects (8.3 h; ratio of geometric means [90% CI]: 1.6 [1.1-2.3]).
• Selexipag and ACT-333679 were highly bound to plasma proteins in subjects with SRI and healthy subjects (unbound fractions of 0.12% and 0.17% for selexipag, and 0.17% and 0.18% for ACT-333679, respectively, with no relevant differences in protein binding between groups).
• Selexipag was generally well tolerated at a single dose of 400 mcg in all subjects. No deaths, serious adverse events, or adverse events (AEs) leading to discontinuation of study were reported. During the study, 5 subjects (62.5%) in each of group A and B had ≥1 AE. Headache was the most frequently reported AE in both groups (4 subjects in each group). All reported AEs were of mild or moderate intensity and had resolved without sequelae by the end of the study. No clinically relevant treatment-related effects on electrocardiogram, urinalysis or clinical laboratory variables were detected. An AE of increased blood pressure was reported for 1 healthy subject. Single dose administration of selexipag appeared to be associated with a transient reduction in supine systolic blood pressure (SBP) and diastolic blood pressure (DBP; median maximum change from baseline in SBP 14.0 mmHg, and in DBP 5.6 mmHg) in subjects with SRI (group A) but had no effect on heart rate (HR).
• Based on these data, the study authors suggested that no adjustment of the starting dose of selexipag is needed for patients with severe renal function impairment. However, the authors did recommend that up-titration be done with caution in this patient population.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 16 January 2025.