Volibris Drug Interactions

Ambrisentan does not inhibit or induce phase I or II drug metabolising enzymes at clinically relevant concentrations in in vitro and in vivo non-clinical studies, suggesting a low potential for ambrisentan to alter the profile of medicinal products metabolised by these pathways.
The potential for ambrisentan to induce CYP3A4 activity was explored in healthy volunteers with results suggesting a lack of inductive effect of ambrisentan on the CYP3A4 isoenzyme.
Cyclosporine A: Steady-state co-administration of ambrisentan and cyclosporine A resulted in a 2-fold increase in ambrisentan exposure in healthy volunteers. This may be due to the inhibition by cyclosporine A of transporters and metabolic enzymes involved in the pharmacokinetics of ambrisentan. Therefore the dose of ambrisentan should be limited to 5 mg once daily when co-administered with cyclosporine A (see Dosage & Administration). Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no dose adjustment of cyclosporine A is warranted.
Rifampicin: Co-administration of rifampicin (an inhibitor of Organic Anion Transporting Polypeptide [OATP], a strong inducer of CYP3A and 2C19, and inducer of P-gp and uridine-diphospho-glucuronosyltransferases [UGTs]) was associated with a transient (approximately 2-fold) increase in ambrisentan exposure following initial doses in healthy volunteers. However, by day 8, steady state administration of rifampicin had no clinically relevant effect on ambrisentan exposure. Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Other targeted PAH treatments: The efficacy and safety of ambrisentan when co-administered with other treatments for PAH (e.g. prostanoids and soluble guanylate cyclase stimulators) has not been specifically studied in controlled clinical trials in PAH patients (see Pharmacology: Pharmacodynamics under Actions). No specific drug-drug interactions with soluble guanylate cyclase stimulators or prostanoids are anticipated based on the known biotransformation data (see Pharmacology: Pharmacokinetics under Actions). However, no specific drug-drug interactions studies have been conducted with these drugs. Therefore, caution is recommended in the case of co-administration.
Phosphodiesterase inhibitors: Co-administration of ambrisentan with a phosphodiesterase inhibitor, either sildenafil or tadalafil (both substrates of CYP3A4) in healthy volunteers did not significantly affect the pharmacokinetics of the phosphodiesterase inhibitor or ambrisentan (see Pharmacology: Pharmacokinetics under Actions).
Oral contraceptives: In a clinical study in healthy volunteers, steady-state dosing with ambrisentan 10 mg once daily did not significantly affect the single-dose pharmacokinetics of the ethinyl estradiol and norethindrone components of a combined oral contraceptive (see Pharmacology: Pharmacokinetics under Actions). Based on this pharmacokinetic study, ambrisentan would not be expected to significantly affect exposure to oestrogen- or progestogen- based contraceptives.
Warfarin: Ambrisentan had no effects on the steady-state pharmacokinetics and anti-coagulant activity of warfarin in a healthy volunteer study (see Pharmacology: Pharmacokinetics under Actions). Warfarin also had no clinically significant effects on the pharmacokinetics of ambrisentan. In addition, in patients, ambrisentan had no overall effect on the weekly warfarin-type anticoagulant dose, prothrombin time (PT) and international normalised ratio (INR).
Ketoconazole: Steady-state administration of ketoconazole (a strong inhibitor of CYP3A4) did not result in a clinically significant increase in exposure to ambrisentan (see Pharmacology: Pharmacokinetics under Actions).
Effect of ambrisentan on xenobiotic transporters: In vitro, ambrisentan has no inhibitory effect on human transporters at clinically relevant concentrations, including the P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), multi-drug resistance related protein 2 (MRP2), bile salt export pump (BSEP), organic anion transporting polypeptides (OATP1B1 and OATP1B3) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP).
Ambrisentan is a substrate for Pgp-mediated efflux.
In vitro studies in rat hepatocytes also showed that ambrisentan did not induce Pgp, BSEP or MRP2 protein expression.
Steady-state administration of ambrisentan in healthy volunteers had no clinically relevant effects on the single-dose pharmacokinetics of digoxin, a substrate for Pgp (see Pharmacology: Pharmacokinetics under Actions).