Macitentan in infants and children with pulmonary hypertensive vascular disease. Feasibility, tolerability and practical issues – a single‐centre experience

Abstract

Macitentan is a safe and effective substance for treatment of adults with pulmonary arterial hypertension. Data on its use in paediatric patients is limited. In this single centre prospective study we report on our experience with macitentan in children focusing on applicability and practical aspects. Between 12/2014 and 07/2018 macitentan was introduced to paediatric patients according to a dosing protocol adjusted to body weight. Blood pressure, heart rate, saturation and clinical symptoms were recorded daily during introduction. Liver function parameters and haemoglobin levels were measured at baseline, 4 weeks and 3 months after initiation and after one year of treatment. 24 patients (14 male, 10 female) were enrolled for treatment with macitentan. The mean age was 10.7 +/- 7.6 years (range 0.1 y – 23 y). 15/24 pts were WHO FC II, 7 pts in FC III and 2 pts in FC IV. 20/24 patients (83%) received additional advanced therapy with sildenafil and /or prostacyclines. We had two early discontinuations because of clinical relevant edema. In the remaining 22 patients macitentan was well tolerated. Liver function parameters and blood count levels remained stable during the observational time. The introduction of macitentan was feasible and mostly well tolerated in paediatric patients. Special attention should be paid to edema during introduction of the drug. To the best of our knowledge, this is the first prospective observational study to report on its applicability in infants and children. However larger prospective trials are warranted to verify these preliminary findings.

Macitentan in the Young—Mid-term Outcomes of Patients with Pulmonary Hypertensive Vascular Disease treated in a Pediatric Tertiary Care Center

“…These two patients were excluded from efficacy analysis. Tolerability and side effects of this substance was reported in detail in our previous work [ 20 ].…”

“…During the past few years, there has been increasing promising experience with macitentan in children [ 16 – 19 ]. We recently reported on practical aspects and safety issues when using macitentan in pediatric patients and now present mid-term effects in children and adolescents with severe PHVD [ 20 ].…”

Pediatric Population Pharmacokinetic Modeling and Exposure–Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data

“…7 Sildenafil, a phosphodiesterase type-5 inhibitor, is approved by the European Medicines Agency for children and adolescents (aged 1-17 years) with PAH, at dosages of 10 mg 3 times daily for body weight 8-20 kg, and 20 mg 3 times daily for body weight ≥20 kg. 25 Macitentan, an endothelial receptor antagonist, 23 and the inhaled prostacyclin analogs treprostinil and iloprost have been used off-label for the treatment of pediatric PAH. 24 Studies in pediatric patients with PAH using the phosphodiesterase type-5 inhibitor, tadalafil, have shown it is well tolerated at doses of up to 20 mg in children aged ≥2 years.…”

“…A number of treatments are available for PAH including bosentan, 7 macitentan, 23 prostacyclin analogs (treprostinil, selexipag, iloprost, beraprost, and epoprostenol), 24 riociguat, sildenafil, 25 and tadalafil 9 . Among these medications, bosentan is the only Food and Drug Administration–approved drug for use in pediatric patients, at dosages up to 31.25 mg twice daily (body weight 10‐20 kg), 62.5 mg twice daily (body weight 20‐40 kg), and 125 mg twice daily (body weight ≥40 kg) 7 .…”

Macitentan attenuates cardiovascular remodelling in infant rats with chronic lung disease

“…Endothelin-1 (ET-1) receptor antagonists offer a promising field of research in preterm chronic lung disease [ 16 , 17 ]. ET-1 is thought to be related to major features of preterm chronic lung disease such as lung fibrosis, impaired alveolarization, and diminished angiogenesis [ 18 , 19 ].…”