Table 3.
Liver metabolism and dose-adjustment of PAH-targeted therapy in patients with hepatic impairment.
| Drug | Liver metabolism | Dose adjustments | ||
|---|---|---|---|---|
| Mild hepatic impairment (Child-Pugh class A) | Moderate hepatic impairment (Child-Pugh class B) | Severe hepatic impairment (Child-Pugh class C) | ||
| Iloprost, inhaled | Increased drug levels in patients with hepatic impairment; not CYP dependent | Consider a starting dose of 2.5 µg and increased dosing intervals (e.g., 3–4 h) | Consider a starting dose of 2.5 µg and increased dosing intervals (e.g., 3–4 h) | Not recommended |
| Treprostinil iv, sc | 2- to 4-fold increase in maximum drug levels in patients with mild to moderate hepatic impairment; drug levels can be influenced by CYP inducer/inhibitors | Initiation dose should be reduced to 0.625 ng/kg/min, increase dose slowly | Initiation dose should be reduced to 0.625 ng/kg/min, increase dose slowly | Not recommended |
| Treprostinil, oral | 1.6-fold increase in maximum drug levels in patients with mild hepatic impairment, 4-fold increase in maximum drug levels in patients with moderate hepatic impairment; drug levels can be influenced by CYP inducer/inhibitors | Start at 0.125 mg twice daily in patients with mild hepatic impairment; avoid in patients with moderate hepatic impairment | Not recommended | Not recommended |
| Selexipag | 1.4-fold increase in maximum drug levels, 2- to 4.5-fold increase in AUC in patients with mild to moderate hepatic impairment; drug levels can be influenced by CYP inducer/inhibitors | No dose adjustment necessary | Start at 200 µg once daily; increase by 200 µg once daily at weekly intervals as tolerated | Contraindicated |
| Riociguat | Minimal increase in maximum drug levels, but 1.5- to 2-fold increase in AUC in patients with moderate hepatic impairment; drug levels can be influenced by CYP inducer/inhibitors | No dose adjustment necessary | Likely increased drug levels, monitor closely for adverse effects | Not recommended |
| Bosentan | 5- to 12-fold increase in maximum drug levels and active metabolite, drug levels can be influenced by CYP inducer/inhibitors; Liver enzymes need to be monitored | Reduce dose if ALT/AST >3 and <5× ULN, stop Bosentan if >5× ULN. | Not recommended | Contraindicated |
| Ambrisentan | Likely increased drug levels in patients with hepatic impairment; drug levels can be influenced by CYP inducer/inhibitors | Discontinue if AST/ALT >5× ULN, or if AST/ALT>2× ULN and increase in total bilirubin | Not recommended | Not recommended |
| Macitentan | Production of active metabolite; associated with slightly reduced plasma levels of active metabolites in patients with hepatic impairment (clinically likely irrelevant); drug levels can be influenced by CYP inducer/inhibitors | Discontinue if AST/ALT >5× ULN, or if AST/ALT>2× ULN and increase in total bilirubin | Not recommended | Not recommended |
| Tadalafil | Likely increased drug levels in patients with hepatic impairment; drug levels can be influenced by CYP inducer/inhibitors | Consider starting dose of 20 mg | Consider starting dose of 20 mg | Not recommended |
| Sildenafil | 1.5-fold increase in maximum drug levels in patients with mild to moderate hepatic impairment; drug levels can be influenced by CYP inducers/inhibitors | No dose adjustment necessary | No dose adjustment necessary | Not recommended |
iv: intravenous; sc: subcutaneous; CYP: cytochrome pathway; AUC: area under the curve; AST/ALT: aspartate transaminase/alanine transaminase; ULN: upper limit of normal.