Carlos Pérez-Ruixo (1), Belén Valenzuela (1), Lene Axelsen (2), Shirin Bruderer (2), Juan José Pérez-Ruixo (1)
1) Janssen Global Clinical Pharmacology, Turnhoutseweg, Beerse, Belgium, (2) Actelion Pharmaceuticals Ltd, Basel, Switzerland
Objectives:
Selexipag is a non-prostanoid, selective prostacyclin receptor agonist approved for use in adults with pulmonary arterial hypertension (PAH). After its oral administration, carboxylesterases in the liver and intestinal wall transform selexipag into ACT-333679, the active metabolite, and the major contributor to drug effect [1]. The objectives of this population pharmacokinetics (PK) analysis were to jointly characterize the time-course of plasma concentrations of selexipag and ACT‐333679, and its corresponding between subjects variability, following oral and intravenous (IV) dosing.
Methods: A total of 20 adult subjects with PAH (4 men, 16 women) were included in the AC-065A309 study, which was an open-label, cross-over, Phase 3 study assessing the safety and tolerability of switching from a stable oral to the corresponding IV dose of selexipag (12.5% higher than the oral dose). Each of the subjects subsequently received oral and IV selexipag. After oral administration, PK sampling protocol included pre-dose, 1,2, 4, 6, 8 and 12 h after drug administration while after IV administration, blood samples were collected at predose and at 0.44, 1.45, 4, 6, 8 and 12 h after drug administration. Selexipag and ACT-333679 were measured using a validated LC-MS/MS assay. A total of 261 selexipag and 263 ACT-333679 plasma concentrations were included in the population PK analysis. The PK data were analysed using non-linear mixed effect modelling approach (NONMEM®) [2] and the model evaluations were performed using prediction corrected visual predictive checks (pcVPC) using PsN [3].
Results:
After IV administration, selexipag PK followed an open linear two-compartment disposition model with a zero-order IV-input into the central compartment and first‑order elimination from the central compartment. ACT-333679 PK was also described with an open linear two‑compartment disposition model with linear elimination from the central compartment. After oral administration, selexipag followed two-pathways absorption, where 63.6% of the dose was absorbed into the central compartment of selexipag through a first order process, characterized by the Ka1, which was estimated to be 0.47 h-1, while the remaining (36.4%) was converted pre-systemically into ACT-333679 and directly absorbed into the central compartment of ACT-333679 following a first-order process, characterized by Ka2, which was estimated to be 0.27 h-1. In addition, the model assumed that selexipag elimination from the central compartment fully accounted for the formation of ACT-333679. Selexipag volume of distribution at steady-state (Vss) and systemic CL were estimated to be 13.0 L and 14.6 L/h, respectively, whereas ACT-333679 Vss and CLm were 70.1 L and 9.24 L/h respectively. The inter-individual variability in model parameters and residual error for selexipag and ACT-333679 concentrations were moderate to large. The results of the pcVPC demonstrated that the population PK model adequately describes the central tendency of the time course of selexipag and ACT-333679 plasma concentration and its associated variability after oral and IV dosing.
Conclusions: The PK of selexipag and ACT-333679 after IV and oral administration in PAH patients was adequately described using an integrated population PK model. The absolute bioavailability of selexipag in PAH patients was estimated to be 63.6%, in line with the value determined by NCA analysis.
References:
[1] Bruderer S et al. Expert Opin Drug Saf (2017) 16: 743-751.
[2] Beal SL et al. 1989-2011. NONMEM Users Guides. Icon Development Solutions, Ellicott City, Maryland, USA.
[3] Lindbom L et al. Comput Methods Programs Biomed. (2004) 75: 85-94.
Reference: PAGE 30 (2022) Abstr 9985 [www.page-meeting.org/?abstract=9985]
Poster: Drug/Disease Modelling - Other Topics