Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension

Abstract

Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomised controlled trials with pulmonary arterial hypertension (PAH)-specific therapies. This study investigated the short-and long-term efficacy/safety of bosentan in these patients, as well as its pharmacokinetics.All 34 consecutive patients with PoPH treated with first-line bosentan (December 2002 to July 2009) were retrospectively evaluated. Assessments included the New York Heart Association functional class (NYHA FC), blood tests, haemodynamics, 6-min walk distance (6MWD) and eventfree status. The pharmacokinetics of bosentan in five patients with Child-Pugh (C-P) class B cirrhosis were compared with idiopathic PAH patients.Significant improvements from baseline were observed in NYHA FC, 6MWD and haemodynamics, and were largely maintained during follow-up. Patients with C-P class B cirrhosis (n59) had significantly larger haemodynamic improvement after mean¡SD 5¡2 months. Mean followup time was 43¡19 months; four patients died and seven patients had significant elevation of liver enzymes (annual rate 5.5%). Plasma concentrations of bosentan were higher in patients with C-P class B cirrhosis than those observed in idiopathic PAH.These data confirm the benefit of bosentan treatment for patients with PoPH. Haemodynamic improvements were particularly pronounced in patients with more severe cirrhosis. The safety profile of bosentan was consistent with previous studies.

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

“…Anecdotal reports suggest that ERAs, PDE-5is, sGC stimulators and prostacyclin analogues may be used in this patient population [214,[350][351][352][353][354][355][356]. This includes potentially hepatotoxic drugs such as bosentan, but it should be noted that this compound tends to accumulate in patients with severely impaired liver function (i.e.…”

“…This includes potentially hepatotoxic drugs such as bosentan, but it should be noted that this compound tends to accumulate in patients with severely impaired liver function (i.e. Child-Pugh class B and C) [356]. Newer ERAs (ambrisentan, macitentan) have a theoretical advantage over bosentan, as the risk of drug-associated liver toxicity is lower [194,201,357], but both drugs have not been systematically evaluated in patients with PoPH.…”

“…The absence of viral particles in the complex plexiform lesions found from these patients suggests that an indirect action of viral infection on inflammation and growth factors may act as a trigger in a predisposed patient. [344] It is recommended that the treatment algorithm for patients with other forms of PAH should be applied to patients with PAH associated with portal hypertension, taking into account the severity of liver disease C I [214,[350][351][352][353][354][355][356] Liver transplantation may be considered in selected patients responding well to PAH therapy C IIb [361][362][363] It is recommended that patients affected by PAH associated with portal hypertension should be referred to centres with expertise in managing both conditions C I [344] Anticoagulation is not recommended in patients with PH associated with portal hypertension C III [365] Liver transplantation is contraindicated in patients with severe and uncontrolled PAH C III [361][362][363] PAH: pulmonary arterial hypertension; PH: pulmonary hypertension. with other risk factors for PAH, such as liver disease (chronic hepatitis B or C), exposure to drugs or toxins or PE due to i.v.…”

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

“…Pojedyncze doniesienia sugerują, że ERA, inhibitory PDE-5, stymulatory rozpuszczalnej cyklazy guanylowej i analogi prostacykliny mogą być stosowane w tej populacji chorych [214,[350][351][352][353][354][355][356]. Zalecenie to obejmuje potencjalnie hepatotoksyczne leki takie jak bosentan, ale należy zauważyć, że związek ten ma tendencję do gromadzenia się u pacjentów z ciężkimi zaburzeniami czynności wątroby (tj.…”

“…Zalecenie to obejmuje potencjalnie hepatotoksyczne leki takie jak bosentan, ale należy zauważyć, że związek ten ma tendencję do gromadzenia się u pacjentów z ciężkimi zaburzeniami czynności wątroby (tj. klasa B i C wg Child-Pugha) [356]. Nowsze ERA (ambrisentan, macitentan) mają teoretyczną przewagę nad bosentanem, a ryzyko uszkodzenia wątroby związane z lekiem jest niższe [194,201,357], ale oba leki nie zostały odpowiednio zbadane u pacjentów z PoPH.…”