SUMMARY

• A single-center, open-label, single-dose, phase 1 study (AC-065-104) investigated the pharmacokinetics, safety, and tolerability of a single dose of 400 mcg selexipag in 16 patients with mild (n=8) or moderate (n=8) hepatic impairment, and a single dose of 200 mcg selexipag in 2 patients with severe hepatic impairment compared to 8 healthy subjects. Study results showed that exposure to selexipag increased 2-fold and 4-fold in patients with mild and moderate hepatic impairment, respectively, when compared to healthy subjects. Exposure to ACT-333679, the main active metabolite of selexipag, remained almost unchanged in patients with mild hepatic impairment and was doubled in patients with moderate hepatic impairment. The safety profile of selexipag in patients with severe hepatic impairment could not be evaluated on the basis of data from only 2 patients.¹
• A real-world analysis assessed the safety profile of UPTRAVI using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Chronic hepatic failure (n=6) and an increase in hepatic enzyme (n=1) were reported in patients.² 
• In the pivotal GRIPHON study investigating the efficacy and safety of UPTRAVI in patients with symptomatic pulmonary arterial hypertension (PAH), patients with moderate or severe hepatic impairment (Child-Pugh B and C) were excluded from participation.³

CLINICAL DATA

Relevant Information Regarding the Pharmacology of Selexipag

After multiple-dose administration, steady-state conditions of selexipag and its active metabolite are reached within 3 days, with no evidence of plasma accumulation.⁴ Maximum observed plasma concentrations of selexipag and its active metabolite after oral administration are reached within 1-3 hours and 3-4 hours, respectively.⁴

Selexipag is rapidly absorbed and is hydrolyzed by carboxylesterases, to its active metabolite, which is 37-fold more potent than selexipag.⁵ In addition, after oral administration, exposure to the active metabolite is 3-4 fold higher than to selexipag at steady state, and it is therefore considered to be the major contributor to the overall activity of the drug.^6,7 Selexipag and its active metabolite both undergo oxidative metabolism by cytochrome P450 (CYP) isoenzymes CYP2C8 and, to a lesser extent, CYP3A4. In addition, the enzymes UDP-glucuronyltransferase (UGT) 1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite.⁸

Study AC-065-104

AC-065-104 was a single-center, open-label, single-dose, phase 1 study to investigate the pharmacokinetics, tolerability, and safety of 400 mcg selexipag in 18 patients with mild (n=8, Child-Pugh class A), moderate (n=8, Child-Pugh class B) or severe hepatic impairment (n=2, Child-Pugh class C) compared to 8 healthy patients.¹ The maximum duration of the study was 6 days for patients with hepatic impairment and 3 days for healthy patients.¹

Patients with mild and moderate hepatic impairment (n=8 each) as well as healthy patients received a single dose of 400 mcg selexipag, and patients with severe hepatic impairment (n=2) received a single dose of 200 mcg selexipag. Dosing was administered in a staggered manner and data was analyzed on day 7 for patients with hepatic impairment and on day 4 for healthy patients.¹

Pharmacokinetic Results

Exposure (AUC_0-∞) to selexipag increased 2-fold and 4-fold in patients with mild hepatic impairment and moderate hepatic impairment, respectively, when compared to healthy subjects. Exposure to ACT-333679, its active metabolite, remained almost unchanged in patients with mild hepatic impairment and was doubled in patients with moderate hepatic impairment.¹ The increase in systemic exposure observed after dosing of patients with moderate hepatic impairment led to a dose reduction to 200 mcg in patients with severe hepatic impairment. Detailed pharmacokinetic results are reported in Table: Plasma Pharmacokinetic Variables of Selexipag and ACT-333679 in Healthy Subjects and Patients with Hepatic Impairment After Administration of a Single Dose of 200 mcg or 400 mcg Selexipag.¹

Safety Results

A total of 14 adverse events (AEs) were reported by 10 patients: 2 AEs by 2 healthy subjects and 12 AEs by 8 patients with hepatic impairment. In particular, 1 patient with severe hepatic impairment reported 2 AEs. Diarrhea, headache, and myalgia were the most frequently reported AEs. No deaths or AEs that led to study discontinuation were reported.¹

One serious AE of hepatic encephalopathy occurred in a patient with severe hepatic impairment who had a recent history of decompensated liver cirrhosis and repeated previous episodes of hepatic encephalopathy. The patient was hospitalized due to hepatic encephalopathy and suspected development of hepatic coma 1 day after single dose of 200 mcg of selexipag. Urinary infection was established as a reason for decompensation and treated with antibiotics. The event resolved without sequelae after 8 days.¹

The overall safety profile of selexipag in patients with severe hepatic impairment could not be evaluated on the basis of data from only 2 patients.¹

Zhao et al (2024)² conducted a real-world analysis that assessed the safety profile of UPTRAVI using the FAERS database from the first quarter of 2016 to the first quarter of 2023. Overall, 281 preferred term (PT) signals were categorized into 20 system organ classes (SOC). Hepatobiliary disorders was identified as 1 of the SOCs affected by UPTRAVI-associated AEs; cases, n=71; signals, n=4; reporting odds ratio (ROR; 95% confidence interval [CI]), 0.81 (0.72-0.91). Chronic hepatic failure, a PT signal, was noted in 6 patients (ROR, 10.74; 95% CI, 4.78-24.12). On assessment of case reports for UPTRAVI-associated adverse drug reactions, 1 patient reported an isolated incident of increased hepatic enzyme.

This study is constrained by several limitations. To begin with, the FAERS is a spontaneous reporting database, thus, compromising the reliability of data quality. Additionally, various unaccounted confounding factors, including potential drug-drug interactions, comorbid conditions, and concurrent medications, were not integrated into the analysis. The statistical associations identified via RORs and Medicines Healthcare Products Regulatory Agency (MHRA) methodologies should not be interpreted as definitive causal links between UPTRAVI and AEs. Also, the FAERS database does not enable the calculation of the true incidence rate of AEs.² Please find the FAERS disclaimer on the following link: FAERS Disclaimer.

GRIPHON

In the pivotal, phase 3 GRIPHON study investigating the efficacy, safety and tolerability of UPTRAVI in patients with symptomatic PAH, patients with moderate or severe hepatic impairment (Child-Pugh B and C) were excluded from participation.³

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases was conducted on 06 March 2025.