Anisa Khan 1, Oscar Della Pasqua 1
1 Clinical Pharmacology & Therapeutics,, University College London (London, United Kingdom )
Objectives: Pulmonary arterial hypertension (PAH) is defined by elevated pulmonary vascular resistance, leading to right heart failure and ultimately death when left untreated. PAH is a rare condition with an estimate prevalence of 15-20 cases per million[1]. Among these, 4-10 cases per million are children[2]. The exact mechanism is not understood, but endothelial cell dysfunction is thought to play a key role[3]. In children, current PAH treatment most commonly involves the use of endothelin receptor antagonists (ERAs), administered either as monotherapy or as part of an early combination regimen, depending on disease severity and clinical response[4].
Macitentan is an orally active and potent dual (ETA and ETB) ERA[1]. Moreover, it undergoes metabolism to form a major pharmacologically active metabolite, ACT-132577. Functional assays have shown that both macitentan and ACT-132577 act as dual receptor antagonists. However, ACT-132577 is approximately fivefold less potent than macitentan at ETA receptors and demonstrates a lower ETA/ETB inhibitory potency ratio compared with its parent compound. Nevertheless, ACT-132577 was developed and approved as a separate drug, aprocitentan (Tryvio, ACT-132577), for the treatment of resistant hypertension in adults[5]. Given that aprocitentan has the same chemical structure as the active metabolite, it is hypothesised that it may also have therapeutic potential in the treatment of PAH[6]. Thus, this study aimed to extrapolate the efficacy based on exposure matching concepts and establish the dose rationale for aprocitentan in children (2–18 years old).
Methods: A nonlinear mixed-effects modelling approach was used alongside simulation and extrapolation principles to predict the pharmacokinetics of aprocitentan in children, assuming comparable exposure-response relationships between adults and paediatric subjects. Pharmacokinetics was evaluated using a published PK model of macitentan in adults and children[7]. The model consisted of an open one-compartment with first-order elimination for macitentan and first-order formation and elimination of aprocitentan. The model was subsequently simplified to describe only aprocitentan disposition properties.
AUC was considered the primary driver of aprocitentan efficacy, whereas Cmax was identified as a determinant of safety[8–10]. Using the final aprocitentan PK model, the median AUC0-24,ss, Css and Cmax predicted in adults were used as target exposure metrics for the paediatric dose selection. Simulation scenarios evaluated various regimens (i.e., fixed, weight-banded and mg/kg doses) to identify doses achieving comparable exposure in both populations. Scenarios included typical adults weighing 65–75kg (n=3000), whereas children were stratified by weight bands (10–20, 20-30, 30–40, 40–50 and 50–60kg) with 1000 children simulated per weight band.
To ensure pharmacological plausibility, maximal endothelin (ET-1) receptor inhibition was also considered as a criterion for the optimisation of the paediatric dosing regimen. Previous clinical studies of macitentan have shown that, at a 10mg dose, the steady-state combined unbound exposure parameter (AUCcombo,0-24,ss)–defined as the sum of macitentan and aprocitentan, weighted by their respective unbound fractions and in vitro potency–is associated with maximal ET-1 receptor inhibition in patients with PAH[9,11]. This AUCcombo,0-24,ss was predicted and subsequently used to determine the equivalent AUCaprocitentan,0-24,ss. All modelling and simulation steps were implemented in NONMEM 7.5 and PsN 5.2.6. Data handling, graphical and statistical summaries were performed in R 4.1.2.
Results: The predicted AUCaprocitentan,0-24,ss in adults was estimated to be 34.0μg*h/mL (25.3–69.4). Additionally, median AUC0-24,ss (90%CI) and Cmax estimates in adults administered the approved dose of 12.5mg aprocitentan was 34.8μg*h/mL (23.4–50.8) and 1.70μg/mL (1.20–2.30), respectively. Since the only approved formulation and strength available is a 12.5mg tablet, the recommended doses were selected based on the development of dispersible, split tablets at the following strengths 12.5mg (split into 2: 6.25mg), 5mg (split into 2: 2.5mg). Thus, the dosing regimen that achieved target AUC0-24,ss (90%CI) comparable to adults, and aligned with the AUCaprocitentan,0-24,ss was as follows: <20kg: 5mg, 20-30kg: 6.25mg, 30–40kg: 7.5mg, 40–50kg: 10mg and 50 – 60kg: 12.5mg. Conclusion: This study illustrates the implementation of extrapolation principles to across compounds to optimise aprocitentan dosing in children with PAH, in line with the recent ICH E11A. While prospective clinical data are needed to confirm use aprocitentan in PAH, these findings highlight the potential impact of model-informed approaches in accelerating evidence generation and improving access to therapies for paediatric patients affected by rare conditions. This study has been supported by ERAMET (https://www.erametproject.eu/). The ERAMET project has received funding from the European Commission’s Horizon Europe Programme under the grant agreement number 101137141. References: 1. Sidharta PN, Treiber A, Dingemanse J. Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan. Clin Pharmacokinet. 2015;54(5):457. 2. Chen Y, Zhang R, Zheng Y, et al. Pediatric pulmonary arterial hypertension: global epidemiology and disease burden during the period 1990 to 2021. Front Cardiovasc Med. 2025;12:1544545. 3. Humbert M, Lau EMT, Montani D, Jaïs X, Sitbon O, Simonneau G. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014;130(24):2189-2208. 4. Berger RMF, Bonnet D, Berger RMF, Bonnet D. Treatment options for paediatric pulmonary arterial hypertension. European Respiratory Review. 2010;19(118):321-330. 5. Angeli F, Verdecchia P, Reboldi G. Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension. Cardiol Ther. 2021;10(2):397. 6. Step. Committee for Medicinal Products for Human Use ICH E11A Guideline on pediatric extrapolation. Published online 2024. 7. Bartolucci R, Dosne AG, Csonka D, Pérez-Ruixo JJ, Magni P, Poggesi I. A Population Pharmacokinetic Model of Macitentan and Its Active Metabolite Aprocitentan in Healthy Volunteers and Patients with Pulmonary Arterial Hypertension. Clinical Pharmacokinetics 2021 60:12. 2021;60(12):1605-1619. 8. Sidharta PN, Melchior M, Kankam MK, Dingemanse J. Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects. Drug Des Devel Ther. 2019;13:949. 9. Goods Administration T. AusPAR Attachment 2 Extract from the Clinical Evaluation Report for macitentan About the Therapeutic Goods Administration (TGA). Published online 2014. 10. Issac M, Dingemanse J, Sidharta PN. Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects. J Clin Pharmacol. 2017;57(8):997-1004. 11. CHMP. Committee for Medicinal Products for Human Use (CHMP) Assessment report on a group of an extension of marketing authorisation and an extension of indication variation. Published online 2024.
Reference: PAGE 34 (2026) Abstr 12117 [www.page-meeting.org/?abstract=12117]
Poster: Drug/Disease Modelling - Paediatrics