Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment

Priska Kaufmann; Hans G Cruz; Andreas Krause; Ivan Ulč; Atef Halabi; Jasper Dingemanse

doi:10.1111/bcp.12963

. 2016 May 10;82(2):369–379. doi: 10.1111/bcp.12963

Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment

Priska Kaufmann ^1,^✉, Hans G Cruz ¹, Andreas Krause ¹, Ivan Ulč ², Atef Halabi ³, Jasper Dingemanse ¹

PMCID: PMC4972153 PMID: 27062188

Abstract

Aim

The aim of the present study was to explore the effect of hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist.

Methods

Two prospective, open‐label studies evaluated the PK of selexipag and its active metabolite ACT‐333679 in healthy subjects and in subjects with mild, moderate and severe hepatic impairment or severe renal function impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration–time profiles.

Results

Exposure increased with the severity of hepatic impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration–time curve from time zero to infinity (AUC_0–∞) for selexipag and ACT‐333679 increased 2.1‐fold (1.7–2.6) and 1.2‐fold (0.9–1.6) in subjects with mild hepatic impairment, and 4.5‐fold (3.4–5.8) and 2.2‐fold (1.7–2.8) in subjects with moderate hepatic impairment when compared with healthy subjects. The two subjects with severe hepatic impairment showed similar dose‐normalized exposure to that of subjects with moderate hepatic impairment. A 1.7‐fold increase in the AUC_0–∞ of selexipag and ACT‐333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT‐333679 was higher in subjects with mild or moderate hepatic impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups.

Conclusions

Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with mild or moderate hepatic impairment or SRFI. However, doses should be up‐titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe hepatic impairment.

Keywords: liver impairment, pharmacokinetics, renal impairment, selexipag

What is Already Known about this Subject

Selexipag (ACT‐293987, NS‐304) is a new, orally active, selective prostacyclin receptor agonist, which targets the prostacyclin pathway and is structurally and pharmacologically distinct from prostanoids. It is currently under clinical development for the treatment of pulmonary arterial hypertension.
The human absorption, distribution, metabolism and excretion (ADME) study showed that most of selexipag is excreted via the biliary route.

What this Study Adds

The results of the study in subjects with hepatic impairment showed that there was an increase in the exposure to selexipag and/or ACT‐333679 with increasing severity of hepatic impairment.
The study revealed an increase in exposure in subjects with severe renal function impairment.
Changes in pharmacokinetics in subjects with mild or moderate hepatic impairment and severe renal function impairment are unlikely to be clinically relevant. No adjustment of the starting dose is needed for patients with such organ impairment. Doses should be up‐titrated with caution in these patients.

Introduction

Prostacyclin, a prostanoid metabolized from endogenous arachidonic acid through the cyclooxygenase (COX) pathway, is a potent vasodilator and also has antiproliferative, antithrombotic and anti‐inflammatory effects 1, 2.

Patients suffering from pulmonary arterial hypertension (PAH) have reduced levels of prostacyclin in the lungs 3, 4, leading to constriction of the pulmonary vasculature and a sustained increase in pulmonary artery pressure, ultimately resulting in right ventricular failure and death 5, 6. Therefore, the restoration of prostacyclin receptor signalling is an effective strategy in the treatment of PAH 7.

Selexipag (ACT‐293987, NS‐304) is an orally available, selective and long‐acting agonist at the prostacyclin receptor (IP receptor). Enzymatic hydrolysis of selexipag by the hepatic carboxylesterase 1 yields ACT‐333679, an active metabolite, which also binds to the IP receptor. It has also been shown that cytochrome P450 (CYP) 2C8 and CYP3A4 are involved in the metabolism of selexipag and ACT‐333679, whereas UDP‐glucuronosyltransferase (UGT) enzymes UGT1A3 and UGT2B7 are also involved in the metabolism of ACT‐333679 8. Selexipag is not expected to have an effect on oral contraceptives, or vice versa. ACT‐333679 has a 13‐fold higher affinity than selexipag for the human IP receptor 9, is at least 16‐fold more potent than selexipag in cellular systems and is highly selective, with an at least 130‐fold lower affinity in vitro for other human prostanoid receptors [e.g. prostaglandin E_1–4 (EP), prostaglandin D₂ (DP) and prostaglandin F (FP) receptors, and the thromboxane A₂ (TXA₂) receptor] compared with the IP receptor 10.

The pharmacokinetics (PK), safety and tolerability of selexipag in healthy subjects have been described previously 8, 11, 12, 13, 14, 15, 16. Results from previous studies indicated that both single‐ and multiple‐dose administration are associated with approximately dose‐proportional PK up to a single dose of 800 μg and multiple doses of up to 1800 μg b.i.d. in healthy subjects. The PK of selexipag and ACT‐333679 are not relevantly affected by gender.

Dose‐limiting adverse events (AEs) in healthy subjects comprised mainly headache, dizziness, nausea and vomiting. The PK profile of selexipag can be described by fast absorption, with peak plasma concentrations (C _max) occurring approximately 2 h after dosing. The apparent elimination half‐life (t_1/2) is 1.3–1.7 h. Selexipag is hydrolysed to ACT‐333679, which is already detectable in plasma 15 min postdose, attaining maximum plasma concentrations about 4 h after single‐ and multiple‐dose administrations 9, 12. Compared with selexipag, the exposure to the metabolite was found to be 3–4 times higher. ACT‐333679 has an apparent elimination t_1/2 of 7.8–9.6 h. After multiple‐dose administration at steady state on day 3, no accumulation of either selexipag or ACT‐333679 was observed 12. Given the high potency and affinity, along with the higher exposure, the active metabolite is considered to be the major contributor to the clinical effects of selexipag in humans.

In vitro studies with cells expressing the recombinant human ether‐a‐go‐go‐related gene (hERG) potassium channels showed no effects of selexipag and ACT‐333679 on hERG channel conductance at concentrations reached in humans. Also, selexipag did not show an effect on cardiac repolarization (QTc interval) or conduction (PR and QRS intervals) and had a mild heart rate‐accelerating effect 13.

A mass balance study has demonstrated that selexipag and its metabolites are excreted almost exclusively via the liver 15, in the faeces. In addition, in animals, biliary excretion was found to be the major route of drug elimination for selexipag. Although renal excretion does not play a major role in the clearance of selexipag and its metabolites, it was also of interest to investigate the effect of severe renal function impairment (SRFI) as renal impairment is a frequent comorbidity in the target PAH patient population for selexipag. In addition, chronic renal impairment may affect the disposition of hepatically cleared drugs 17.

Two clinical studies were conducted to assess the effects of varying degrees of hepatic impairment and SRFI on the PK, safety and tolerability of selexipag.

Methods

Study 1: hepatic impairment

Study design

This was a prospective, open‐label, single‐dose, single‐centre phase I study. Following the screening assessments, subjects were admitted to the study centre on day −1 and were treated with selexipag on day 1 with a planned single dose of 400 μg. For safety reasons, subjects with less severe hepatic impairment were treated first. After an interim analysis of the PK, safety and tolerability data for the previous group, the dose could be adjusted for the next group. Subjects were observed in the study centre for 3 days or 6 days, and were discharged at the end of study (i.e. day 4 for healthy subjects, day 7 for subjects with hepatic impairment), at which time the excretion of selexipag and its metabolites should have been complete.

After review of the interim PK results of subjects with moderate hepatic impairment (group B), which revealed a relevant increase in the exposure to selexipag and ACT‐333679 compared with healthy subjects, the dose in subjects with severe hepatic impairment (group C) was reduced to 200 μg in order to mitigate any potential risk.

Subjects

After eligibility screening, male and female subjects with hepatic cirrhosis were categorized based on Child–Pugh classification as having mild, moderate or severe hepatic impairment, and were allocated to groups A, B and C 18. Child–Pugh grading was based on laboratory test results at screening for serum bilirubin, albumin, prothrombin time (PT) and the stage of hepatic encephalopathy, with or without the presence of ascites 19. These results of the Child–Pugh classification had to be confirmed on day −1, if the screening assessment had taken place more than 1 week before day 1.

Eight healthy subjects (based on medical history and screening examination) were enrolled in control group D. Each subject in group D was matched with one subject in the moderate hepatic impairment group (group B) based on age (±5 years), body weight (±10%), height (±10%) and gender. Enrolment of matched healthy subjects was performed after all subjects with hepatic impairment had completed all study procedures.

The accepted age range was 30–75 years (inclusive) and the body mass index (BMI) of the subjects was required to be between 18 kg m⁻² and 32 kg m⁻². Subjects were required to have a normal age‐adjusted renal function at screening, confirmed by creatinine clearance (CL_cr) estimated using the Cockroft–Gault formula 20, 21.

Subjects with clinical evidence of any medical condition potentially interfering with the absorption, distribution, metabolism or excretion (ADME) of the study drug, except for those related to liver cirrhosis, were not enrolled in the study. Concomitant medication had to be stable prior to screening in patients with hepatic impairment. For healthy subjects, no concomitant medication was allowed at least 2 weeks prior to screening, except for contraceptives and hormone replacement therapy. Women of childbearing potential had to have a negative pregnancy test at screening and on day −1, and had to be using a reliable method of contraception up to 28 days after study drug intake. Pregnant or breastfeeding women were ineligible, as well as subjects with excessive caffeine intake, regular cigarette smokers and subjects with positive results from alcohol breath and urine drug tests at screening or on day −1. Subjects were also excluded if they had a known hypersensitivity to any excipients of the drug formulation, had received any investigational drug within 3 months prior to dosing, had a positive HIV serology at screening or had lost ≥250 ml blood within 3 months prior to screening. Further exclusion criteria comprised clinically relevant electrocardiogram (ECG) abnormalities, illness or organ disorders, except from those related to hepatic impairment for groups A–C, or concomitant medications that might reasonably influence the results of the trial.

During the time in the study centre, subjects received standardized meals; the drinking of alcoholic or xanthine‐containing beverages was not permitted. From screening until the end of the study examination, smoking was not permitted and subjects had to refrain from strenuous sporting activities.

The study was approved by the national health authority of the Czech Republic and an independent ethics committee (Ethics Committee of CEPHA, Pilsen, Czech Republic, reference number CPA 383–10). It was conducted in accordance with the Declaration of Helsinki and local laws and regulations. Written informed consent was received from all subjects prior to enrolment in the study.

Blood sampling

Blood samples for PK assessments were taken at 0 h (predose), and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 48 and 72 h postdose for all subjects, and then at 96, 120 and 144 h postdose for subjects with hepatic impairment. For assessment of plasma protein binding, additional blood samples were collected at 3 h postdose, predicted to be in between the two values of the time to reach C _max (T _max) of 2 h and 4 h for both analytes.

Bioanalytical methods

Selexipag and ACT‐333679 were quantified in plasma using a validated liquid chromatography with tandem mass spectrometry (LC–MS/MS) method as described previously 12. As part of the sampling process, plasma was acidified with 1 M hydrochloric acid. The method was linear in the concentration range 0.01–20.0 ng ml⁻¹ for both selexipag and ACT‐333679. The lower limit of quantification (LOQ) was 0.01 ng ml⁻¹ for both selexipag and ACT‐333679.

Quality control (QC) samples were analysed and their measured concentrations were used to determine the between‐run and overall precision, and the accuracy of the analyses. Precision [coefficient of variation (% CV)] was ≤11.0% and 10.8% for selexipag and ACT‐333679, respectively, whereas accuracy ranged from 98.7% to 103.1% for selexipag and from 99.3% to 103.3% for ACT‐333679.

The unbound fraction (C _u/C) of selexipag and ACT‐333679 in plasma was determined using equilibrium dialysis followed by analyses with a validated LC–MS/MS method. Aliquots of 200 μl plasma and 350 μl of phosphate‐buffered saline buffer were loaded into the plasma and buffer chamber, respectively, on a rapid equilibrium dialysis device (Thermo Fisher Scientific, Waltham, MA, USA) and incubated for 4 h at 37 °C. For concentration measurements of these samples, the same LC–MS/MS system was used as described above for the plasma concentration determination, although with slight adaptations of the mobile phase gradients and the MS/MS settings. Samples were quantified using peak area ratios. This LC–MS/MS method was validated over the concentration range 2.00–2000 pg ml⁻¹ for both analytes, with an LOQ of 2.00 pg ml⁻¹. Analyses of QC samples showed that the method was precise and accurate. The interbatch precision was ≤10.9% and 11.1% for selexipag and ACT‐333679, respectively, whereas the interbatch accuracy was in the range 97.6–107.0% of nominal concentration for selexipag and 98.6–103.3% for ACT‐333679.

PK and statistical evaluations

The sample size of eight subjects per group was based on empirical considerations. The following plasma PK parameters were derived by noncompartmental analysis of the concentration–time profiles of selexipag and its active metabolite ACT‐333679 using Phoenix WinNonlin software Version 6.1 (Pharsight Corporation, Cary, NC, USA): C _max, T _max, t_½ and area under the concentration–time curve from time zero to infinity (AUC_0–∞). Both C _max, and T _max, were obtained directly from the measured individual plasma concentrations of selexipag and ACT‐333679, AUC_0–∞ was calculated by combining AUC_0–t and AUC_extra, where AUC_0–t was estimated by the linear trapezoidal rule using the measured concentration–time values above the LOQ, and AUC_extra represents an extrapolated value obtained by dividing the last plasma concentration measured above the LOQ by the terminal elimination rate constant, determined by log‐linear regression analysis of the measured plasma concentrations of the terminal elimination phase (C_t/λ_z). The t_½ of selexipag and ACT‐333679 were calculated as follows: t_½ = In 2/λ_z.

The PK parameters C _max, AUC and t_½ were assumed to be log‐normally distributed 22 and summarized using geometric means and their two‐sided 95% confidence interval (CI). The median and range values were used for T _max. Differences in C _max, AUC_0–∞, C _u/C and t_½ between healthy subjects and hepatic impairment groups were explored using the ratios of geometric means and their 90% CI (healthy subject results were considered as reference). For the PK analyses, the concentration‐dependent PK parameters (AUC, C _max) were dose adjusted, which enabled the comparison of the PK parameters between groups. Based on the assumption that the PK of selexipag were also dose proportional in this study population, AUC and C _max values in group C were multiplied by two to obtain comparable data 12. On an exploratory basis, the ratios of the geometric means and 90% CI of the AUC_0–∞ for ACT‐333679 and selexipag were calculated.

The safety and tolerability of the study drug were evaluated throughout the study and analysed descriptively.

Study 2: renal impairment

Study design

This was a prospective, single‐centre, parallel group, open‐label, single‐dose phase I study, similar to study 1, described above.

For safety reasons, a staggered approach was used. Four subjects with SRFI in group A received 400 μg selexipag first (with an interval of 24 h between the first two subjects and the remaining two subjects in this subgroup) followed by the treatment of four healthy matched subjects 5–6 days later. After evaluation of the PK, safety and tolerability data for this group, the four remaining subjects with SRFI and their healthy matched controls were treated with selexipag. No dose reduction for the second subgroup of subjects with SRFI was required.

Since urine creatinine clearance calculated using timed urine collections (e.g., over 24 h) does not improve estimates of glomerular filtration rate (GFR) in the population enrolled into this study over that provided by prediction equations, is not suitable for routine clinical practice or clinical trials 23, and as exposure of subjects to additional exogenous compounds should be limited, renal function was defined by the estimated glomerular filtration rate (eGFR) at screening using the Modification of Diet in Renal Disease (MDRD) formula.

Subjects

SRFI subjects were included if their eGFR was <30 ml min⁻¹ 1.73 m⁻² and for healthy subjects a normal renal function was defined by eGFR ≥90 ml min⁻¹ 1.73 m⁻². The eGFR was confirmed on day −1 if screening assessments had taken place more than 1 week before day 1. Subjects with SRFI were excluded if they required dialysis, had a haemoglobin concentration ˂9 g dl⁻¹ or if they had to follow strict fluid restriction (˂1000 ml 24 h⁻¹). A total of eight subjects (both male and female) with SRFI, required to be between 18 and 79 years of age, with a BMI between 18 kg m⁻² and 35 kg m⁻² and a body weight of at least 50 kg at screening, were enrolled in the study (group A). Eight healthy age‐ (±10 years), BMI‐ (±15%), race‐ and gender‐matched subjects with normal renal function served as a control group (group B).

Subjects were not permitted to take any creatine supplements from screening until the end of the study. Other general inclusion and exclusion criteria were as defined for study 1. The study was conducted according to the Declaration of Helsinki and local laws and regulations, and was approved by the German national health authority and by an independent ethics committee (Ethikkommission bei der Ärztekammer Schleswig‐Holstein, Bad Segeberg, Germany, reference number 079/11 [II]). Written informed consent was obtained from all subjects prior to the start of the study.

Blood sampling

Blood samples for PK assessment were taken at 0 h (predose), and then at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48 and 72 h postdose for all subjects and, in addition, at 96, 120 and 144 h postdose for subjects with SRFI. For assessment of plasma protein binding, an additional blood sample was collected at 3 h postdose.

Bioanalytical methods

The same bioanalytical methods were applied as described above for study 1.

PK and statistical evaluations

The sample size was based on empirical considerations. For calculation of the PK parameters and group comparisons, the same methods were used as described for study 1. Safety and tolerability were assessed throughout the study and reported descriptively.

Results

Study 1: hepatic impairment

Demographics

Overall, 17 male and nine female subjects were included in four groups. Eight subjects (six male, two female) in group A (mild hepatic impairment), eight subjects (five male, three female) in group B (moderate hepatic impairment), two subjects (one male, one female) in group C (severe hepatic impairment) and eight (five male, three female) in group D (matched healthy subjects). After the occurrence of a serious adverse event (SAE) in a subject with severe hepatic impairment, no further subjects with severe hepatic impairment were treated. All subjects included in the study were evaluable for PK, safety and tolerability.

Baseline demographics of age, weight and height were similar across all four groups. A high proportion of subjects in groups A–C received concomitant medication at baseline to treat their hepatic condition, including bile acid preparations, sulphonamides and gastric ulcer prophylactic agents. These subjects were also prescribed treatments for their comorbidities present at baseline, including diuretics and angiotensin‐converting enzyme inhibitors. One healthy female subject in group D used hormonal contraceptives.

Tolerability and safety

There were no deaths or AEs leading to study discontinuation of subjects. A total of 14 AEs were reported by 10 subjects: two AEs by two healthy subjects and 12 by eight subjects with varying degrees of hepatic impairment. Three subjects in group A (37.5%) reported four AEs, four subjects in group B (50%) reported six AEs, one subject in group C (50%) reported two AEs and two subjects in group D (25%) reported two AEs. Diarrhoea, headache and myalgia were the most frequently reported AEs. One subject with severe hepatic impairment and a medical history of decompensated liver cirrhosis with repeated episodes of hepatic encephalopathy experienced an SAE of hepatic encephalopathy in the context of a urinary tract infection, which was diagnosed and evaluated as a possible reason for decompensation. A relationship with study medication could not be excluded and therefore the SAE was considered to be related to study medication.

AEs were more frequent in subjects with hepatic impairment when compared with healthy subjects. Except for one case of moderate diarrhoea and one case of severe hepatic encephalopathy, as described above, all AEs were of mild intensity. All AEs resolved without sequelae and did not require treatment, except for the severe case of hepatic encephalopathy.

No clinically relevant treatment‐related changes in clinical laboratory variables, body weight or ECG variables were observed during the study. Single‐dose administration of selexipag appeared to decrease blood pressure in healthy subjects (median maximum change from baseline in systolic blood pressure (SBP) –7.0 mmHg, and in diastolic blood pressure (DBP) –5.5 mmHg) as well as in subjects with hepatic impairment (median maximum change from baseline in SBP −13.5 mmHg, and in DBP −8.5 mmHg) without an apparent effect on heart rate (HR).

PK

Visual inspection of the mean selexipag and ACT‐333679 concentration–time profiles indicated that these were similar in shape for healthy subjects and those with mild hepatic impairment. By contrast, following attainment of maximum concentrations, the decrease in selexipag and ACT‐333679 plasma concentrations was markedly slower in subjects with moderate or severe hepatic impairment (Figure 1).

Arithmetic mean plasma concentration vs. time profiles of selexipag (top) and ACT‐333679 (bottom) in healthy subjects (n = 8, group D) and subjects with mild (n = 8, group A), moderate (n = 8, group B) or severe (n = 2, group C) hepatic impairment after administration of a single dose of 200 μg or 400 μg selexipag. The semi‐logarithmic scale is shown as an insert within each panel. () Group A 400 μg, () Group B 400 μg, () Group C 200 μg, () Group D 400 μg

Inline graphic — Arithmetic mean plasma concentration vs. time profiles of selexipag (top) and ACT‐333679 (bottom) in healthy subjects (n = 8, group D) and subjects with mild (n = 8, group A), moderate (n = 8, group B) or severe (n = 2, group C) hepatic impairment after administration of a single dose of 200 μg or 400 μg selexipag. The semi‐logarithmic scale is shown as an insert within each panel. () Group A 400 μg, () Group B 400 μg, () Group C 200 μg, () Group D 400 μg

The PK parameters of selexipag and ACT‐333679, obtained by noncompartmental analysis, are summarized in Table 1. The geometric mean ratios of PK parameters and their 90% CIs, obtained by analysis, using healthy subjects (group D) as a reference, are shown in Table 2.

Table 1.

Plasma pharmacokinetic parameters of selexipag and ACT‐333679 in healthy subjects and subjects with hepatic impairment after administration of a single oral dose of 200 μg or 400 μg selexipag

Analyte	Group	n	C _max [ ng ml ⁻¹ ]	T _max [h]	AUC _0–∞ [h ng ml ⁻¹ ]	t _1/2 [h]	C _u /C [%]
Selexipag	A	8	3.9 (2.8, 5.3)	1.0 (1.0–4.0)	10.9 (8.6, 13.8)	1.6 (1.3, 2.1)	0.55 (0.46, 0.65)
	B	8	5.4 (3.9, 7.4)	2.0 (1.0–6.0)	23.3 (17.0, 32.4)	2.2 (1.6, 3.0)	0.73 (0.53, 1.02)
	C	2	4.4* (NC)	2.0 (1.0–3.0)	NC (NC)	NC (NC)	1.00 (NC)
	D	8	1.9 (1.5, 2.4)	1.0 (1.0–2.0)	5.2 (4.5, 6.2)	1.1 (0.8, 1.4)	0.56 (0.43, 0.74)
ACT‐333679	A	8	4.5 (3.1, 6.7)	5.0 (3.0–6.0)	29.6 (20.6, 42.6)	6.5 (4.9, 8.7)	0.63 (0.54, 0.73)
	B	8	5.3 (4.6, 6.0)	6.0 (4.0–7.0)	56.1 (42.8, 73.5)	15.9 (10.1, 25.0)	0.86 (0.63, 1.18)
	C	2	4.7* (NC)	5.5 (5.0–6.0)	73.8* (NC)	7.3 (NC)	1.30 (NC)
	D	8	3.8 (3.0, 5.0)	4.0 (4.0–6.0)	25.3 (21.9, 29.3)	12.6 (9.1, 17.5)	0.64 (0.49, 0.84)

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A, subjects with mild hepatic impairment; B, subjects with moderate hepatic impairment; C, subjects with severe hepatic impairment; D, healthy subjects. For group C, summary statistics for two subjects were calculated. Data are expressed as geometric means (95% confidence interval) and for T _max median (range). Groups A, B and D received a single dose of 400 μg, whereas subjects in group C received a single dose of 200 μg. AUC_0–∞, area under the plasma concentration–time curve from zero to infinity; C _max, maximum plasma concentration; C _u/C, unbound fraction; NC, not calculated; t_1/2, elimination half‐life; T _max, time to reach C _max.

The C _max and AUC_0–∞ values of group C were multiplied by two in order to correct for dose.

Table 2.

Comparison of pharmacokinetic parameters of selexipag and ACT‐333679 in healthy subjects and subjects with hepatic impairment after administration of a single oral dose of 200 μg or 400 μg selexipag

Analyte	Pharmacokinetic variable	n	Comparison	Geometric mean ratio (90% CI)
Selexipag	C _max [ng ml⁻¹]	8/8	A : D	2.01 (1.51, 2.70)
		8/8	B : D	2.79 (2.09, 3.74)
		2/8	C* : D	2.30 (0.57, 3.36)
	AUC_0–∞ [h ng ml⁻¹]	8/8	A : D	2.08 (1.68, 2.57)
		8/8	B : D	4.46 (3.41, 5.84)
		1/8	C* : D	NC
	t_1/2 [h]	8/8	A : D	1.52 (1.14, 2.04)
		8/8	B : D	2.06 (1.48, 2.85)
		1/8	C : D	NC
	C _u/C [%]	8/8	A : D	0.97 (0.76, 1.24)
		8/8	B : D	1.30 (0.94, 1.79)
		2/8	C : D	1.79 (1.13, 2.82)
ACT‐333679	C _max [ng ml⁻¹]	8/8	A : D	1.18 (0.84, 1.67)
		8/8	B : D	1.37 (1.10, 1.71)
		2/8	C* : D	1.22 (0.78, 1.91)
	AUC_0–∞ [h ng ml⁻¹]	8/8	A : D	1.17 (0.87, 1.56)
		8/8	B : D	2.22 (1.76, 2.78)
		2/8	C* : D	2.91 (2.01, 4.23)
	t_1/2 [h]	8/8	A : D	0.51 (0.37, 0.71)
		8/8	B : D	1.27 (0.83, 1.92)
		2/8	C : D	0.58 (0.33, 1.01)
	C _u/C [%]	8/8	A : D	0.98 (0.78, 1.23)
		8/8	B : D	1.34 (0.99, 1.82)
		2/8	C : D	2.01 (1.29, 3.14)

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A, subjects with mild hepatic impairment; B, subjects with moderate hepatic impairment; C, subjects with severe hepatic impairment; D, healthy subjects matched to group B. AUC_0–∞, area under the plasma concentration–time curve from zero to infinity; CI, confidence interval; C _max, maximum plasma concentration; C _u/C, unbound fraction; NC, not calculated; t_1/2, elimination half‐life; T _max, time to C _max..*The C _max and AUC_0–∞ values for group C were multiplied by two in order to correct for dose.

Exposure to selexipag doubled in subjects with mild hepatic impairment compared with healthy subjects, whereas exposure to ACT‐333679 was similar in both groups. Plasma selexipag concentrations were markedly increased in subjects with moderate hepatic impairment. The median T _max was longer than in healthy subjects (2.0 vs. 1.0 h), and the elimination phase was characterized by a longer t_½ (2.2 vs. 1.1 h). Overall, this resulted in a more than fourfold increase in exposure (AUC_0–∞) to selexipag in subjects with moderate hepatic impairment compared with healthy subjects. The PK of ACT‐333679 were also affected by moderate hepatic impairment but to a smaller extent. The exposure (AUC_0–∞) was increased more than two‐fold, and both median T _max and t_½ also increased (6.0 vs. 4.0 h and 15.9 vs. 12.6 h, respectively). The two subjects with severe hepatic impairment showed similar exposure (AUC_0–∞), T _max and t_½, compared with the subjects with moderate hepatic impairment, when taking into account the lower dose they received. For within‐group comparisons of the exposure to the metabolite and the parent compound, the geometric mean ratios (90% CI) for groups A, B and D were 2.7 (1.4, 5.2), 2.4 (1.3, 4.4) and 4.8 (3.8, 6.1), respectively.

The geometric mean percentages of free selexipag and ACT‐333679 (groups A–D) ranged from 0.55% to 1.00%, and 0.63% to 1.30%, respectively. Levels of unbound compound increased with the severity of hepatic impairment.

Study 2: renal impairment

Demographics

Eight subjects with SRFI and eight matched healthy subjects were enrolled (four male and four female subjects in each group), completed the study as per protocol and were included in all the subsequent analyses.

Baseline demographics of age, weight and height were similar across the two groups. At screening, subjects with SRFI had an eGFR of 15–29 ml min⁻¹ 1.73 m⁻² and healthy subjects had an eGFR of 90–141 ml min⁻¹ 1.73 m⁻².

All subjects received a single dose of 400 μg selexipag. Subjects with SRFI were taking medications related to their renal disease and other comorbidities; these included sodium bicarbonate, epoetin alpha, alfacalcidol, furosemide, allopurinol, antihypertensive agents (amlodipine, enalapril, ramipril, metoprolol, hydrochlorothiazide), simvastatin and insulin.

Tolerability and safety

There were no deaths, SAEs or study discontinuations. Seventeen AEs were reported during the study by 10 subjects. Five subjects in group A (62.5%) reported eight AEs, and five subjects in group B (62.5%) reported nine AEs. All of these were of mild or moderate intensity and resolved without sequelae and with no treatment required. Headache was the most frequently reported AE, and was reported by four subjects (50%) in each group.

No clinically relevant treatment‐related effects on ECG, urinalysis or clinical laboratory variables were detected. At baseline, subjects with SRFI showed differences for ECG, urinalysis, haematology and clinical chemistry compared with healthy subjects, which were consistent with the underlying medical conditions.

No clinically relevant mean changes from baseline in vital signs were observed in the two groups. An AE of increased blood pressure was reported for one healthy subject. Single‐dose administration of selexipag appeared to be associated with a transient reduction in supine SBP and DBP (median maximum change from baseline in SBP −14.0 mmHg, and in DBP −5.6 mmHg) in subjects with SRFI (group A) but had no effect on HR. This reduction in blood pressure was only observed at a single time‐point (2 h after dosing) and was not observed in healthy subjects.

PK

Plasma concentrations of selexipag and ACT‐333679 were higher in subjects with SRFI (group A) compared with healthy subjects (group B) (Figure 2).

Arithmetic mean plasma concentration vs. time profiles of selexipag (top) and ACT‐333679 (bottom) in healthy subjects (n = 8, group B) and subjects with severe renal function impairment (n = 8, group A) after administration of a single dose of 400 μg selexipag. The semi‐logarithmic scale is shown as an insert within each panel. () Group A 400 μg, () Group B 400 μg

Selexipag was absorbed with a median T _max of 2.0 h and 1.5 h in SRFI and healthy subjects, respectively, and a 1.7‐fold increase in exposure (C _max and AUC_0–∞) to selexipag was observed in subjects with SRFI compared with healthy subjects. Selexipag t_½ in subjects with SRFI compared with healthy subjects (1.4 h vs. 1.0 h, respectively) can be regarded as similar, taking into account the between‐subject variability of this parameter. The metabolite ACT‐333679 had a similar median T _max (4.0 h and 4.5 h) in SRFI and healthy subjects, respectively. Similar to selexipag, for ACT‐333679 a 1.4‐fold increase in C _max and a 1.6‐fold increase in exposure (AUC_0–∞) was observed in subjects with SRFI compared with healthy subjects. ACT‐333679 had a longer t_½ in subjects with SRFI compared with healthy subjects (13.4 h vs. 8.3 h). In subjects with SRFI, the PK of both selexipag and ACT‐333679 were affected to a similar extent and did not lead to a change in metabolic ratio. Selexipag and its active metabolite ACT‐333679 were highly bound to plasma proteins in subjects with SRFI 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) (Table 3).

Table 3.

Plasma pharmacokinetic variables of selexipag and ACT‐333679 in healthy subjects and subjects with severe renal function impairment after administration of a single oral dose of 400 μg selexipag

Analyte	Group	C _max [ ng ml ⁻¹ ]	T _max [h]	AUC _0–∞ [h ng ml ⁻¹ ]	t _1/2 [h]	C _u /C [%]
Selexipag	Healthy	3.1 (2.1, 4.5)	1.5 (0.5–6.0)	9.9 (7.4, 13.2)	1.0 (0.7, 1.5)	0.17 (0.00, 13.87)
	SRFI	5.4 (3.9, 7.4)	2.0 (1.0–5.0)	17.1 (13.5, 21.6)	1.4 (0.8, 2.2)	0.12 (0.04, 0.43)
	Geometric mean ratio (SRFI : healthy)	1.7 (1.2, 2.5)		1.7 (1.3, 2.3)	0.8 (0.5, 1.2)	0.73 (0.16, 3.41)
ACT‐333679	Healthy	5.12 (3.2, 8.3)	4.5 (2.0–8.0)	43.7 (14.6, 131.1)	8.3 (7.0, 9.9)	0.18 (0.12, 0.03)
	SRFI	7.3 (6.1, 8.7)	4.0 (1.5–6.0)	70.6 (29.3, 170.3)	13.4 (7.1, 25.4)	0.17 (0.11, 0.29)
	Geometric mean ratio (SRFI : healthy)	1.4 (1.0, 2.1)		1.6 (0.6, 4.2)	1.6 (1.1, 2.3)	1.03 (0.65, 1.62)

Open in a new tab

Data are geometric means (95% CI), except for geometric mean ratios, where the CI was 90%, and for T _max, where medians (range) are given. AUC_0–∞, area under the plasma concentration–time curve from zero to infinity; CI, confidence interval; C _max, maximum plasma concentration; C _u/C, unbound fraction; SRFI, severe renal function impairment; T _max, time to C _max; t_1/2, elimination half‐life.

Discussion

The two studies reported here investigated the PK, safety and tolerability of selexipag in subjects with hepatic or renal impairment after a single dose of 400 μg, which corresponds to the highest well‐tolerated single dose in healthy subjects 14. Results from previous studies in healthy subjects indicate that both single‐ and multiple‐dose administrations are associated with approximately dose‐proportional PK up to a single dose of 800 μg and multiple doses of up to 1800 μg b.i.d. 12.

The objective of the present study was to give treating physicians guidance on the safety of the starting dose or dosing regimen as both hepatic and renal impairment comorbidities may be present in patients with PAH, the target population of selexipag. In the pivotal phase III trial, selexipag was used at an individualized dose of 200–1600 μg b.i.d., reached after weekly up‐titration steps 24, 25, 26. Gradual up‐titration to an individual patient's highest tolerated dose is the generally accepted regimen for IP receptor agonists 27, 28. Initiating treatment with high doses of these compounds is associated with reduced or poor tolerability due to typical acute prostacyclin‐associated pharmacological effects such as headache, diarrhoea, jaw pain, myalgia, flushing, nausea and hypotension. Thus, selexipag is not administered at a fixed dose and, in the case of the occurrence of undesired target or off‐target effects, further up‐titration is stopped. Administration of up to 1600 μg given twice daily leads to a considerably higher exposure than a single dose of 400 μg in patients with moderate hepatic impairment, and safety and tolerability have been thoroughly assessed up to 1600 μg b.i.d. 11, 12, 13. Twice‐daily administration does not lead to accumulation of selexipag or ACT‐333679. Therefore, the exposure seen in patients with moderate hepatic impairment at this low single dose in the context of a drug undergoing up‐titration is of no concern as long as safety and tolerability are confirmed. As the safe and well‐tolerated dose of 400 μg investigated in the present study is above the starting dose of 200 μg used in clinical practice, no adjustment of the starting dose is warranted 12, 25, 26.

In the present study, exposure to ACT‐333679, the active metabolite that is the major contributor to the clinical effects of selexipag in humans, was less affected by hepatic impairment compared with selexipag, which is also reflected by a change in the metabolic ratio of AUC_0–∞ between those with hepatic impairment and healthy subjects. In subjects with mild or moderate liver impairment, exposure to selexipag was increased two‐ and four‐fold, respectively, whereas exposure to the metabolite was similar to that seen in healthy subjects with mild hepatic impairment and only doubled in subjects with moderate impairment. The observed increase in AUC_0–∞ for selexipag and/or ACT‐333679 in subjects with mild or moderate hepatic impairment was a consequence of combined increases in C _max and t_1/2. These findings are in accordance with the fact that metabolism is driven by hepatic enzymes and the results of the ADME study, which showed that following administration of radiolabelled selexipag, 93% of the total radioactivity was excreted in faeces, whereas only 12% of the dose was found in the urine 15, emphasizing the importance of hepatic metabolism and/or biliary elimination. Subjects with severe hepatic impairment (Child–Pugh C) received a reduced dose of 200 μg. These two subjects showed similar exposure, T _max and t_½ compared with the subjects with moderate hepatic impairment, when taking into account the lower dose they received. However, after the occurrence of an SAE in a subject with severe hepatic impairment, no further subjects with severe hepatic impairment were treated. The decision not to recruit further subjects was driven mainly by consideration given to the poor health and frailty of seriously ill patients, rather than a concrete risk related to the compound. Information on subjects with severe hepatic impairment is too limited to draw firm conclusions.

In subjects with SRFI, the PK of both selexipag and ACT‐333679 were affected to a similar extent. Exposures were, on average, 1.6–1.7‐fold higher for AUC_0–∞ and 1.4–1.7‐fold higher for C _max in SRFI subjects compared with healthy subjects.

Comparing the two studies, there was a difference in exposure (AUC_0–∞ and C _max) to selexipag in the group of healthy subjects. However, exposures of healthy subjects measured in both studies were within the range of variability observed in other selexipag studies 8, 12, 14. It is of note that the two studies were run at different sites, with different subjects, and the variability between subjects and studies is not unusual. In a different study, the intersubject variability for selexipag AUC (%) was estimated to be 43% 11.

On the basis of the results obtained in the ADME study 15, which showed excretion of the majority of selexipag via the liver, it was anticipated that impaired liver function would affect the PK of selexipag. The results confirmed the relevance of hepatic metabolism in the elimination of selexipag. However, they also showed that chronic renal disease should not be considered as an isolated condition that affects only drugs excreted via the kidney. Renal disease not only has the potential to alter the renal clearance of unchanged drug, but may also modify the metabolic transformation and transport of drugs in both the liver and the kidneys 29, 30, 31.

In previous studies, hepatic or renal impairment has been shown to decrease the levels of plasma protein binding of several drugs 32, 33, 34. Selexipag and ACT‐333679 were highly protein bound, which is consistent with the results of in vitro studies. In the studies described here, SRFI and mild hepatic impairment had little effect on the unbound fraction of selexipag or ACT‐333679, whereas in subjects with moderate hepatic impairment the unbound fraction increased by approximately 30%. It has been reported, mainly for drugs given parenterally with a high hepatic extraction ratio and a high volume of distribution, that changes in protein binding might influence the PK of the compound. As selexipag does not fall into this category, the reduced plasma protein binding observed in the present study in subjects with moderate hepatic impairment is not expected to be clinically significant 35, 36. As noted before, information on subjects with severe hepatic impairment is too limited to draw firm conclusions.

There is limited information available on the PK of other drugs targeting the prostacyclin pathway in subjects with renal or hepatic impairment. Treprostinil (oral, subcutaneous) has been studied in subjects with varying degrees of hepatic impairment. Adjustments to the starting dose are deemed necessary in those with mild and moderate hepatic impairment, and consideration should be given to a slower dose titration schedule 37. No clinically relevant differences in the PK of oral treprostinil were found in subjects with end‐stage renal disease requiring dialysis compared with healthy subjects 38.

For iloprost, special caution has to be exercised during initial dose titration in subjects with hepatic impairment. In addition, consideration should be given to increasing the dosing interval 39. In subjects with a CL_cr > 30 ml min⁻¹ (using the Cockroft–Gault formula), there is no need for dose adaptation. There are no data for subjects with a CL_cr of ≤30 ml min⁻¹ 39.

Overall, selexipag was well tolerated at the administered dose, and in both studies the safety profile of selexipag was similar to that observed in other studies. With the exception of the SAE occurring in a subject with severe hepatic impairment, all AEs were of mild or moderate intensity. It should be noted that the small number of subjects limited the data on selexipag in subjects with severe hepatic impairment. The most frequent AEs were similar to those previously associated with prostacyclin and its analogues, and in line with AEs seen in other clinical studies of selexipag (e.g. headache, diarrhoea, myalgia). All AEs resolved without sequelae. The reduction in median changes from baseline in SBP and DBP observed in subjects with renal or hepatic impairment are considered to be related to the vasodilatory properties of prostacyclin receptor agonists. The more pronounced reduction in blood pressure in patients compared with healthy subjects suggests that subjects with hepatic or renal impairment are possibly more susceptible to the vasodilatory effect of selexipag. However, none of the changes were considered clinically relevant. No apparent effect on HR was noted, which is in line with in vivo and in vitro studies that showed no evidence of relevant effects on ventricular repolarization 13.

In conclusion, exposure to selexipag is higher in subjects with SRFI or mild and moderate hepatic impairment. In order to assess the potential clinical impact of impaired organ function, ACT‐333679, the active metabolite of selexipag and the major contributor to the clinical effects in man, should be considered. The PK profile of ACT‐333679 is affected less than its parent compound by impaired hepatic and renal organ function. Based on the results of these studies in subjects with mild or moderate hepatic impairment or SRFI, the AEs reported following a single dose of selexipag 400 μg were consistent with the known safety profile of selexipag, and the detected increase in exposure was not associated with any unexpected AEs. In clinical practice, the proposed up‐titration regimen starts with a dose of 200 μg. Therefore, the PK data suggest that the clinically used starting dose needs no adjustments in patients with mild or moderate hepatic impairment or SRFI. Consideration should perhaps be given to extending the dosing interval for patients with moderate or severe hepatic impairment. A PK model estimated similar exposure to selexipag and ACT‐333679 during once‐daily dosing in patients with moderate or severe hepatic impairment compared with healthy subjects, and during twice‐daily dosing in patients with mild hepatic impairment. As selexipag is titrated based on each patient's individual tolerability and experience of AEs, the physician and patient will be able to decide whether a particular dose of selexipag is tolerable. However, it should be noted that doses should be up‐titrated with caution in these patients.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: PK, HC, AK and JD had support from Actelion Pharmaceuticals Ltd for the submitted work; PK, AK and JD were employed by and held stock options for Actelion Pharmaceuticals Ltd in the previous 3 years; AH had support from Clinical Research Services Kiel GmbH, sponsored by Actelion Pharmaceuticals Ltd, for the submitted work and was employed by Clinical Research Services Kiel GmbH in the previous 3 years; IU had support from CEPHA s.r.o., sponsored by Actelion Pharmaceuticals Ltd for the submitted work and was employed by CEPHA s.r.o. in the previous 3 years; there were no other relationships or activities that could appear to have influenced the submitted work.

This study was sponsored by Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. Some preclinical data were generated by Nippon Shinyaku, Kyoto, Japan. The authors thank Pavla Kadlecová (ADDS, Brno, Czech Republic) for the statistical analysis of clinical and PK data, and Dr Christoph Siethoff and the staff of SwissBioQuant AG (Reinach, Switzerland) for conducting the bioanalytical work.

Contributors

All authors were involved in the data collection, analysis and/or interpretation; critically revised the manuscript and approved the final version for publication.

Kaufmann, P. , Cruz, H. G. , Krause, A. , Ulč, I. , Halabi, A. , and Dingemanse, J. (2016) Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment. Br J Clin Pharmacol, 82: 369–379. doi: 10.1111/bcp.12963.

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[bcp12963-bib-0001] 1. Galiè N, Negro L, Simonneau G. The use of combination therapy in pulmonary arterial hypertension: new developments. Eur Respir Rev 2009; 18: 148–53. [DOI] [PubMed] [Google Scholar]

[bcp12963-bib-0002] 2. Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009; 54: S10–9. [DOI] [PubMed] [Google Scholar]

[bcp12963-bib-0003] 3. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992; 327: 70–5. [DOI] [PubMed] [Google Scholar]

[bcp12963-bib-0004] 4. Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S. Pathology of pulmonary hypertension. Clin Chest Med 2007; 28: 23–42, VII. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bcp12963-bib-0005] 5. Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol 2008; 44: 14–30. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bcp12963-bib-0006] 6. Schannwell CM, Steiner S, Strauer BE. Diagnostics in pulmonary hypertension. J Physiol Pharmacol 2007; 58: 591–602. [PubMed] [Google Scholar]

[bcp12963-bib-0007] 7. Gomberg‐Maitland M, Olschewski H. Prostacyclin therapies for the treatment of pulmonary arterial hypertension. Eur Respir J 2008; 31: 891–901. [DOI] [PubMed] [Google Scholar]

[bcp12963-bib-0008] 8. Kaufmann P, Niglis S, Bruderer S, Segrestaa J, Aanismaa P, Halabi A, et al. Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects. Br J Clin Pharmacol 2015; 80: 670–7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bcp12963-bib-0009] 9. Kuwano K, Hashino A, Asaki T, Hamamoto T, Yamada T, Okubo K, et al. 2‐[4‐[(5,6‐diphenylpyrazin‐2‐yl)(isopropyl)amino]butoxy]‐N‐(methylsulfonyl)acetamide (NS‐304), an orally available and long‐acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007; 322: 1181–8. [DOI] [PubMed] [Google Scholar]

[bcp12963-bib-0010] 10. Skoro‐Sajer N, Lang IM. Selexipag for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother 2014; 15: 429–36. [DOI] [PubMed] [Google Scholar]

[bcp12963-bib-0011] 11. Baldoni D, Bruderer S, Muhsen N, Dingemanse J. Bioequivalence of different dose‐strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple‐dose up‐titration study. Int J Clin Pharmacol Ther 2015; 53: 788–98. [DOI] [PubMed] [Google Scholar]

[bcp12963-bib-0012] 12. Bruderer S, Hurst N, Kaufmann P, Dingemanse J. Multiple‐dose up‐titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects. Pharmacology 2014; 94: 148–56. [DOI] [PubMed] [Google Scholar]

[bcp12963-bib-0013] 13. Hoch M, Darpo B, Remenova T, Stoltz R, Zhou M, Kaufmann P, et al. A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist. Drug Des Devel Ther 2015; 9: 175–85. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bcp12963-bib-0014] 14. Kaufmann P, Okubo K, Bruderer S, Mant T, Yamada T, Dingemanse J, et al. Pharmacokinetics and tolerability of the novel oral prostacyclin IP receptor agonist selexipag. Am J Cardiovasc Drugs 2015; 15: 195–203. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bcp12963-bib-0015] 15. Kaufmann P, Okubo K, Sidharta PN, Yamada T, Dingemanse J, Mukai H. Investigation of the absorption, metabolism, and excretion of 14^C‐selexipag following oral administration to healthy male subjects. Clin Pharmacol Ther 2012; 91: Supplement S1, page S85. [Google Scholar]

[bcp12963-bib-0016] 16. Niglis S, Bruderer S, Okubo K, Mukai H, Dingemanse J. Investigation of potential pharmacodynamic and pharmacokinetic interactions between selexipag and warfarin in healthy male subjects. Clin Pharmacol Drug Dev 2013; 2: Supplement 1, page 3. [DOI] [PubMed] [Google Scholar]

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PERMALINK

Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment

Priska Kaufmann

Hans G Cruz

Andreas Krause

Ivan Ulč

Atef Halabi

Jasper Dingemanse

Abstract

Aim

Methods

Results

Conclusions

What is Already Known about this Subject

What this Study Adds

Introduction

Methods

Study 1: hepatic impairment

Study design

Subjects

Blood sampling

Bioanalytical methods

PK and statistical evaluations

Study 2: renal impairment

Study design

Subjects

Blood sampling

Bioanalytical methods

PK and statistical evaluations

Results

Study 1: hepatic impairment

Demographics

Tolerability and safety

PK

Figure 1.

Table 1.

Table 2.

Study 2: renal impairment

Demographics

Tolerability and safety

PK

Figure 2.

Table 3.

Discussion

Competing Interests

Contributors

References

ACTIONS

PERMALINK

RESOURCES

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