No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers

Spence, Rebecca; Mandagere, Arun; Harrison, Brooke C.; Dufton, Christopher; Boinpally, Ramesh

doi:10.1002/jps.21789

Cited by 56 publications

(31 citation statements)

References 21 publications

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“…Concomitant administration of bosentan and sildenafil has been shown to result in a 63 % decrease in the AUC of sildenafil and a 50 % increase in the AUC of bosentan [64]. Ambrisentan and tadalafil, when taken together, do not significantly impact each other's pharmacokinetics [65]. When macitentan and sildenafil are taken in combination, there is a 15 % decrease in the AUC of macitentan and a 15 % increase in the AUC of sildenafil [66].…”

Section: Phosphodiesterase-5 Inhibitorsmentioning

confidence: 97%

Comparative Safety and Tolerability of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension

2015

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Pulmonary arterial hypertension (PAH) is a condition that leads to progressive right heart failure and death unless recognized and treated early. Endothelin, a potent endogenous vasoconstrictor, has been identified as an important mediator of PAH. Endothelin receptor antagonists (ERAs) have been associated with an improvement in exercise capacity and time to clinical worsening in patients with Group 1 PAH, and three different ERAs are currently approved for use in this population: bosentan, ambrisentan, and macitentan. While all three ERAs are generally well-tolerated, they each have important adverse effects that need to be recognized and monitored. In particular, they may cause anemia, peripheral edema, and mild cardiac, respiratory, neurologic, and gastrointestinal adverse effects to varying degrees. Although bosentan increases a patient's risk of developing liver transaminitis, ambrisentan and macitentan do not appear to confer the same risk of hepatotoxicity at this time. Important drug-drug interactions, particularly involving other drugs metabolized via the cytochrome P450 pathway, are important to recognize when prescribing ERAs. In this review, we provide a brief overview of the current state of knowledge as it relates to the adverse effect profiles, tolerability, and drug-drug interactions of this class of medication as informed by the results of randomized clinical trials, drug surveillance programs, and regulatory agencies.

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Section: Phosphodiesterase-5 Inhibitorsmentioning

confidence: 97%

Comparative Safety and Tolerability of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension

2015

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“…We chose this combination because ambrisentan, 17 a selective endothelin-Areceptor antagonist, and tadalafil, 18 a phosphodiesterase type 5 inhibitor, target different intracellular pathways and do not have pharmacokinetic interactions. 19 …”

mentioning

confidence: 99%

Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension

et al. 2015

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BACKGROUNDData on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce. METHODSIn this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentanmonotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. RESULTSThe primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooledmonotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, −67.2% vs. −50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONSAmong participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.)

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“…Unlike bosentan, ambrisentan does not interact with either tadalafil or sildenafil (Spence et al, 2008(Spence et al, , 2009. As a result, a 33-patient open-label trial (ATHENA-1) was conducted to evaluate whether the addition of 24 weeks of ambrisentan will improve PVR (primary endpoint) in patients with PAH who have a suboptimal response with PDE-5 inhibitor monotherapy .…”

Section: Ambrisentan a Clinical Studies Ambrisentan (Letairis) Is Amentioning

confidence: 99%

The Pharmacological Treatment of Pulmonary Arterial Hypertension

Frumkin

2012

Pharmacological Reviews

106

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No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers

Cited by 56 publications

References 21 publications

Comparative Safety and Tolerability of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension

Comparative Safety and Tolerability of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension

Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension

The Pharmacological Treatment of Pulmonary Arterial Hypertension

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