Table 5 Monitoring and dosage of pulmonary arterial hypertension pharmacotherapy in hepatic impairment

Sildenafil [8]

Extensive hepatic metabolism (CYP3A4 major; CYP2C9 minor); active metabolite (which is 50% ==as active as sildenafil) also undergoes hepatic metabolism

No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied

Hypotension; worsening of side effects (epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea and/or rhinitis)

Hold or reduce dose if patient presents with acute liver injury and hypotension.

Tadalafil [11]

Hepatic metabolism via CYP3A to inactive metabolites (which undergo methylation and glucuronidation)

Child-Pugh class A or B: reduce starting dose to 20 mg once per day

Hypotension; worsening of side effects (headache)

Hold or reduce dose if patient presents with acute liver injury and hypotension

Child-Pugh class C: avoid use

Ambrisentan [17]

Hepatic metabolism via CYP3A, CYP2C19, and UGTs 1A9S, 2B7S an 1A3S; substrate OATP1B1 and OATP1B3; substrate but not an inhibitor of P-glycoprotein

Not recommended in patients with moderate or severe hepatic impairment

Peripheral edema/fluid overload, nasal congestion, sinusitis and/or flushing

Package labeling recommendation: discontinue if aminotransferase elevations >5× ULN or if elevations are accompanied by bilirubin >2× ULN, or by signs or symptoms of liver dysfunction and other causes are excluded

Bosentan [13]

Eliminated by biliary excretion following metabolism in the liver; three metabolites (one active); induces CYP2C9, CYP34 and possibly CYP2C19. Thought to induce its own metabolism

Child-Pugh class A: no dosage adjustment required

Peripheral edema/fluid overload, anemia, respiratory tract infections

Package labeling: ALT/AST >5× and <8× ULN, stop treatment and monitor ALT/AST levels at least every 2 weeks. Once the ALT/AST levels return to pretreatment values, consider reintroduction of the treatment

Child-Pugh class B or C: avoid use

ALT/AST >8× ULN: discontinue treatment indefinitely

Macitentan [13]

Metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on CYP3A4 (major) and CYP2C19 (minor)

No adjustment necessary

Anemia, nasopharyngitis, pharyngitis, bronchitis, headache, influenza, and urinary tract infection

Package labeling: if clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2× ULN, or by clinical symptoms of hepatotoxicity, discontinue macitentan. Consider reinitiation when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity

Riociguat [19]

Metabolized by CYP1A1, CYP3A, CYP2C8 and CYP2J2. Formation of the major active metabolite, M1, is catalyzed by CYP1A1; M1 is further metabolized to the inactive N-glucuronide.

Child-Pugh class A or B: no dosage adjustment required. Child-Pugh class B or C: no data available

Hypotension, bleeding or other side effects (headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation)

Hold or reduce dose if patient presents with significant acute liver injury and hypotension

Epoprostenol [39],[40]

Rapid metabolism via hydrolysis at neutral pH in blood (major), also subject to enzymatic degradation (minor); two minimally active metabolites (one from hydrolysis, one from enzymatic degradation)

No adjustment necessary; if initiating therapy, consider starting at the low end of the dosing range and titrating slowly

Possible hypotension or side effects (headache, jaw pain, flushing)

Probably safe for use in patients with liver dysfunction; consider dosage reduction if patient is hypotensive and is experiencing increased side effects (flushing, headache, jaw pain); do not abruptly discontinue therapy

Treprostinil [41]

Hepatic metabolism via CYP2C8 (major) and via oxidation and glucuronidation (minor)

Mild to moderate hepatic insufficiency: initial dose should be decreased to 0.625 ng/kg/minute ideal body weight; cautious dosage increase

Hypotension or side effects (headache, jaw pain, flushing)

Exposure is increased in patients with hepatic insufficiency; if patient presents with acute liver injury and signs of increased drug exposure (hypotension, headache, flushing, jaw pain, and so forth), cautiously and gradually decrease dosage until symptoms subside. Do not abruptly discontinue therapy. One reasonable approach is to decrease the treprostinil dose by 10% every 3 hours until symptoms improve

Severe hepatic insufficiency: no studies performed

Nitric oxide, inhaled [42]

Nonhepatic elimination

No dosage adjustments recommended/required

Methemoglobin

Probably safe to use in patients with hepatic dysfunction

Treprostinil, inhaled [21]

Hepatic metabolism via CYP2C8 (major) and via oxidation and glucuronidation (minor)

Mild-moderate hepatic impairment: up-titrate slowly when initiating. Severe hepatic insufficiency: no studies performed

Hypotension or worsening of side effects (headache, jaw pain, flushing)

Exposure is increased in patients with hepatic insufficiency; if patient presents with acute liver injury and signs of increased drug exposure (hypotension, headache, flushing, jaw pain, and so forth), increase dosing interval and/or decrease inhalations per treatment until symptoms subside

Iloprost, inhaled [20]

Hepatic metabolism via β-oxidation (major) and cytochrome P450 (minor); major metabolite is inactive

Child-Pugh class B or C: consider increasing the dosing interval (for example, 3 to 4 hours between doses depending on the patient’s response at the end of the dose interval)

Hypotension/syncope, headache, flushing, ALP/GGT increased, flu-like symptoms, hemoptysis, muscle pain/cramping

Exposure is increased in patients with hepatic insufficiency; if patient presents with acute liver injury and signs of increased drug exposure (hypotension, headache, jaw pain, and so forth), consider increasing the dosing interval until symptoms subside