CLINICAL PHARMACOLOGY
Mechanism Of Action
Selexipag is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from
prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which
is approximately 37-fold as potent as selexipag. Selexipag and the active metabolite are selective
for the IP receptor versus other prostanoid receptors (EP1-4, DP, FP, and TP).
Pharmacodynamics
Cardiac Electrophysiology
At the maximum tolerated dose of 1600 mcg twice daily, selexipag does not prolong the QT
interval to any clinically relevant extent.
Platelet Aggregation
Both selexipag and its active metabolite caused concentration-dependent inhibition of platelet
aggregation in vitro with an IC50 of 5.5 μM and 0.21 μM, respectively. However, at clinically
relevant concentrations, there was no effect on platelet aggregation test parameters as seen
following multiple-dose administrations of selexipag in healthy subjects from 400 mcg up to 1800
mcg twice daily.
Pulmonary Hemodynamics
A Phase 2 clinical study assessed hemodynamic variables after 17 weeks of treatment in patients
with PAH WHO Functional Class II–III and concomitantly receiving endothelin receptor
antagonists (ERAs) and/or phosphodiesterase type 5 (PDE-5) inhibitors. Patients titrating
selexipag to an individually tolerated dose (200 mcg twice daily increments up to 800 mcg twice
daily) (N=33) achieved a statistically-significant mean reduction in pulmonary vascular resistance
of 30.3% (95% confidence interval [CI] −44.7%, −12.2%) and an increase in cardiac index
(median treatment effect) of 0.41 L/min/m2 (95% CI 0.10, 0.71) compared to placebo (N=10).
Drug Interaction
In a study in healthy subjects, selexipag (400 mcg twice a day) did not influence the
pharmacodynamic effect of warfarin on the international normalized ratio.
Pharmacokinetics
The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy
subjects. The pharmacokinetics of selexipag and the active metabolite, after both single- and
multiple-dose administration, were dose-proportional up to a single dose of 800 mcg and multiple
doses of up to 1800 mcg twice daily.
In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing
interval, AUC) at steady-state was 43% and 39% for selexipag and the active metabolite,
respectively. Intra-subject variability in exposure was 24% and 19% for selexipag and the active
metabolite, respectively.
Exposures to selexipag and the active metabolite at steady-state in PAH patients and healthy
subjects were similar. The pharmacokinetics of selexipag and the active metabolite in PAH
patients were not influenced by the severity of the disease and did not change with time.
Both in healthy subjects and PAH patients, after oral administration, exposure at steady-state to
the active metabolite is approximately 3- to 4-fold that of selexipag. Exposure to the active
metabolite is approximately 30% higher after oral administration compared to the same
intravenous dose in healthy subjects.
Absorption
The absolute bioavailability of selexipag is approximately 49%. Upon oral administration,
maximum observed plasma concentrations of selexipag and its active metabolite are reached
within about 1–3 hours and 3–4 hours, respectively.
In the presence of food, the absorption of selexipag was prolonged resulting in a delayed time to
peak concentration (Tmax) and ~30% lower peak plasma concentration (Cmax). The exposure to
selexipag and the active metabolite (AUC) did not significantly change in the presence of food.
Distribution
The volume of distribution of selexipag at steady state is 11.7 L.
Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in
total and to the same extent to albumin and alpha1-acid glycoprotein).
Metabolism
Selexipag is hydrolyzed to its active metabolite, (free carboxylic acid) in the liver and intestine by
carboxylesterases. Oxidative metabolism, catalyzed mainly by CYP2C8 and to a smaller extent
by CYP3A4, leads to the formation of hydroxylated and dealkylated products. UGT1A3 and
UGT2B7 are involved in the glucuronidation of the active metabolite. Except for the active
metabolite, none of the circulating metabolites in human plasma exceeds 3% of the total drugrelated
material.
Elimination
Elimination of selexipag is predominately via metabolism with a mean terminal half-life of 0.8-2.5
hours. The terminal half-life of the active metabolite is 6.2-13.5 hours. There is minimal
accumulation of the active metabolite upon twice daily repeat administration suggesting that the
effective half-life is in the range of 3-4 hours. The total body clearance of selexipag is 17.9 L/hour.
Excretion
In a study in healthy subjects with radiolabeled selexipag, approximately 93% of radioactive drug
material was eliminated in feces and only 12% in urine. Neither selexipag nor its active metabolite
were found in urine.
Specific Populations
No clinically relevant effects of sex, race, age or body weight on the pharmacokinetics of selexipag
and its active metabolite have been observed in healthy subjects or PAH patients.
Age
The pharmacokinetic variables (Cmax and AUC) were similar in adult and elderly subjects up to 75
years of age. There was no effect of age on the pharmacokinetics of selexipag and the active
metabolite in PAH patients.
Hepatic Impairment
In subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment,
exposure to selexipag was 2- and 4-fold that seen in healthy subjects. Exposure to the active
metabolite of selexipag remained almost unchanged in subjects with mild hepatic impairment and
was doubled in subjects with moderate hepatic impairment [see Use In Specific Populations].
Based on pharmacokinetic modeling of data from a study in subjects with hepatic impairment, the
exposure to the active metabolite at steady state in subjects with moderate hepatic impairment
(Child-Pugh class B) after a once daily regimen is expected to be similar to that in healthy subjects
receiving a twice daily regimen. The exposure to selexipag at steady state in these patients during
a once daily regimen is predicted to be approximately 2-fold that seen in healthy subjects receiving
a twice-daily regimen.
Renal Impairment
A 40-70% increase in exposure (maximum plasma concentration and area under the plasma
concentration-time curve) to selexipag and its active metabolite was observed in subjects with
severe renal impairment (estimated glomerular filtration rate ≥ 15 mL/min/1.73 m2 and < 30
mL/min/1.73 m2) [see Use In Specific Populations].
Drug Interaction Studies
In Vitro Studies
Selexipag is hydrolyzed to its active metabolite by carboxylesterases. Selexipag and its active
metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by
CYP3A4. The glucuronidation of the active metabolite is catalyzed by UGT1A3 and UGT2B7.
Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a
substrate of P-gp, and the active metabolite is a substrate of the transporter of breast cancer
resistance protein (BCRP).
Selexipag and its active metabolite do not inhibit or induce cytochrome P450 enzymes and
transport proteins at clinically relevant concentrations.
The effect of moderate inhibitors of CYP2C8 on the exposure to selexipag or its active metabolite
has not been studied. Concomitant administration with moderate inhibitors of CYP2C8 may result
in a significant increase in exposure to selexipag and its active metabolite[see DRUG INTERACTIONS].
The results on in vivo drug interaction studies are presented in Figure 1 and 2.
Figure 1: Effect of Other Drugs on UPTRAVI and its Active Metabolite
 |
*ERA and PDE-5 inhibitor data from GRIPHON. |
Clinical Studies
Pulmonary Arterial Hypertension
The effect of selexipag on progression of PAH was demonstrated in a multi-center, double-blind,
placebo-controlled, parallel group, event-driven study (GRIPHON) in 1156 patients with
symptomatic (WHO Functional Class I [0.8%], II [46%], III [53%], and IV [1%] ) PAH. Patients
were randomized to either placebo (N = 582), or UPTRAVI (N = 574). The dose was increased in
weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to
1600 mcg twice a day.
The primary study endpoint was the time to first occurrence up to end-of-treatment of: a) death, b)
hospitalization for PAH, c) PAH worsening resulting in need for lung transplantation, or balloon
atrial septostomy, d) initiation of parenteral prostanoid therapy or chronic oxygen therapy, or e)
other disease progression based on a 15% decrease from baseline in 6MWD plus worsening of
Functional Class or need for additional PAH-specific therapy.
The mean age was 48 years, the majority of patients were white (65%) and female (80%). Nearly
all patients were in WHO Functional Class II and III at baseline.
Idiopathic or heritable PAH was the most common etiology in the study population (58%)
followed by PAH associated with connective tissue disease (29%), PAH associated with congenital
heart disease with repaired shunts (10%), drugs and toxins (2%), and HIV (1%).
At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of an
endothelin receptor antagonist (15%), a PDE-5 inhibitor (32%), or both (33%).
Patients on selexipag achieved doses within the following groups: 200-400 mcg (23%), 600-1000
mcg (31%) and 1200-1600 mcg (43%).
Treatment with UPTRAVI resulted in a 40% reduction (99% CI: 22 to 54%; two-sided log-rank
p-value < 0.0001) of the occurrence of primary endpoint events compared to placebo (Table 2;
Figure 3). The beneficial effect of UPTRAVI was primarily attributable to a reduction in
hospitalization for PAH and a reduction in other disease progression events (Table 2). The
observed benefit of UPTRAVI was similar regardless of the dose achieved when patients were
titrated to their highest tolerated dose [see DOSAGE AND ADMINISTRATION].
Figure 3 Kaplan-Meier Estimates of the First Morbidity-Mortality Event in
GRIPHON
Table 2 Primary Endpoints and Related Components in GRIPHON
|
UPTRAVI
N=574 |
Placebo
N=582 |
Hazard Ratio
(99% CI) |
p-value |
n |
% |
n |
% |
|
|
Primary endpoint events up to the end of treatment |
All primary endpoint events |
155 |
27.0 |
242 |
41.6 |
0.60 [0.46,0.78] |
<0.0001 |
As first event: |
|
78 |
13.6 |
109 |
18.7 |
|
|
- Other disease Progression
(Decrease in 6MWD plus
worsening functional class or
need for other therapy)
|
38 |
6.6 |
100 |
17.2 |
|
|
|
28 |
4.9 |
18 |
3.1 |
|
|
- Parenteral prostanoid or
chronic oxygen therapy
|
10 |
1.7 |
13 |
2.2 |
|
|
- PAH worsening resulting in
need for lung transplantation
or balloon atrial septostomy
|
1 |
0.2 |
2 |
0.3 |
|
|
It is not known if the excess number of deaths in the selexipag group is drug-related because there
were so few deaths and the imbalance was not observed until 18 months into GRIPHON.
Figures 4A, B, and C show time to first event analyses for primary endpoint components of
hospitalization for PAH (A), other disease progression (B), and death (C)—all censored 7 days
after any primary end point event (because many patients on placebo transitioned to open-label
UPTRAVI at this point).
Figure 4 A Hospitalization for PAH as the First Endpoint in GRIPHON
Figure 4B Disease Progression as the First Endpoint in GRIPHON
Figure 4C Death as the First Endpoint in GRIPHON
The treatment effect of UPTRAVI on time to first primary event was consistent irrespective of
background PAH therapy (i.e., in combination with an ERA, PDE-5i, both, or without background
therapy) (Figure 5).
Figure 5 Subgroup Analyses of the Primary Endpoint in GRIPHON
 |
Note: Race group “Other” is not displayed in analysis, as the population is less than 30. EU = Number of UPTRAVI
patients with events, NU = Number of patients randomized to UPTRAVI, EP = Number of Placebo patients with
events, NP = Number of patients randomized to Placebo, HR = Hazard Ratio, CI = Confidence Interval, the size of
the squares represent the number of patients in the subgroup.
Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all were prespecified.
The 99% confidence limits that are shown do not take into account how many comparisons were made, nor
do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or
heterogeneity among groups should not be over-interpreted. |
6-Minute Walk Distance (6MWD)
Exercise capacity was evaluated as a secondary endpoint. Median absolute change from baseline
to week 26 in 6MWD measured at trough (i.e., at approximately 12 hours post-dose) was +4 meters
with UPTRAVI and -9 meters in the placebo group. This resulted in a placebo-corrected median
treatment effect of 12 meters (99% CI: 1, 24 meters;two-sided p = 0.005).