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Mechanism Of Action
Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance.
In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH.
Ambrisentan is a high-affinity (Ki=0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor ( > 4000-fold). The clinical impact of high selectivity for ETA is not known.
In a randomized, positive-and placebo-controlled, parallel-group study, healthy subjects received either Letairis 10 mg daily followed by a single dose of 40 mg, placebo followed by a single dose of moxifloxacin 400 mg, or placebo alone. Letairis 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of Letairis increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. For patients receiving Letairis 5–10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected.
The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects is dose proportional. The absolute bioavailability of ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately 2 hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that ambrisentan is a substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl ambrisentan accounts for approximately 4% relative to parent ambrisentan AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although ambrisentan has a 15-hour terminal half-life, the mean trough concentration of ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of ambrisentan is about 9 hours.
In Vitro Studies
Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is a substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, and P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, a clinically relevant interaction has been demonstrated only with cyclosporine [see DRUG INTERACTIONS]. In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC50 of 47 μM, 45 μM, and approximately 100 μM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations.
In Vivo Studies
The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure 2 and Figure 3, respectively.
Figure 2 : Effects of Other Drugs on Ambrisentan
* Omeprazole: based on population pharmacokinetic analysis in PAH patients
** Rifampin: AUC and Cmax were measured at steady-state. On Day 3 of coadministration a transient 2-fold increase in AUC was noted that was no longer evident by Day 7. Day 7 results are presented.
Figure 3 : Effects of Ambrisentan on Other Drugs
* Active metabolite of mycophenolate mofetil ** GMR (95% CI) for INR
Pulmonary Arterial Hypertension (PAH)
Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted in 393 patients with PAH (WHO Group 1). The two studies were identical in design except for the doses of Letairis and the geographic region of the investigational sites. ARIES-1 compared once-daily doses of 5 mg and 10 mg Letairis to placebo, while ARIES-2 compared once-daily doses of 2.5 mg and 5 mg Letairis to placebo. In both studies, Letairis or placebo was added to current therapy, which could have included a combination of anticoagulants, diuretics, calcium channel blockers, or digoxin, but not epoprostenol, treprostinil, iloprost, bosentan, or sildenafil. The primary study endpoint was 6-minute walk distance. In addition, clinical worsening, WHO functional class, dyspnea, and SF-36® Health Survey were assessed.
Patients had idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%), HIV infection (3%), or anorexigen use (1%). There were no patients with PAH associated with congenital heart disease.
Patients had WHO functional class I (2%), II (38%), III (55%), or IV (5%) symptoms at baseline. The mean age of patients was 50 years, 79% of patients were female, and 77% were Caucasian.
Submaximal Exercise Ability
Results of the 6-minute walk distance at 12 weeks for the ARIES-1 and ARIES-2 studies are shown in Table 2 and Figure 4.
Table 2 : Changes from Baseline in 6-Minute Walk
(N = 67)
(N = 67)
(N = 67)
(N = 65)
(N = 64)
(N = 63)
|Baseline||342 ± 73||340 ± 77||342 ± 78||343 ± 86||347 ± 84||355 ± 84|
|Mean change from baseline||-8 ± 79||23 ± 83||44 ± 63||-10 ± 94||22 ± 83||49 ± 75|
|Placebo-adjusted mean change from baseline||-||31||51||-||32||59|
|Placebo-adjusted median change from baseline||-||27||39||-||30||45|
|p-valuea||-||0.008||< 0.001||-||0.022||< 0.001|
|Mean ± standard deviation
a p-values are Wilcoxon rank sum test comparisons of Letairis to placebo at Week 12 stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients
Figure 4 : Mean Change in
6-Minute Walk Distance
Mean change from baseline in 6-minute walk distance in the placebo and Letairis groups Values are expressed as mean ± standard error of the mean.
In both studies, treatment with Letairis resulted in a significant improvement in 6-minute walk distance for each dose of Letairis and the improvements increased with dose. An increase in 6-minute walk distance was observed after 4 weeks of treatment with Letairis, with a dose-response observed after 12 weeks of treatment. Improvements in walk distance with Letairis were smaller for elderly patients (age ≥ 65) than younger patients and for patients with secondary PAH than for patients with idiopathic or heritable PAH. The results of such subgroup analyses must be interpreted cautiously.
The effects of Letairis on walk distances at trough drug levels are not known. Because only once-daily dosing was studied in the clinical trials, the efficacy and safety of more frequent dosing regimens for Letairis are not known. If exercise ability is not sustained throughout the day in a patient, consider other PAH treatments that have been studied with more-frequent dosing regimens.
Time to clinical worsening of PAH was defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape. Early escape was defined as meeting two or more of the following criteria: a 20% decrease in the 6-minute walk distance; an increase in WHO functional class; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure; or refractory systolic hypotension. The clinical worsening events during the 12-week treatment period of the Letairis clinical trials are shown in Table 3 and Figure 5.
Table 3 : Time to Clinical Worsening
(N = 67)
(N = 134)
(N = 65)
(N = 127)
|Clinical worsening, no. (%)||7 (10%)||4 (3%)||13 (22%)||8 (6%)|
|p-value, Fisher exact test||-||0.044||-||0.006|
|p-value, Log-rank test||-||0.030||-||0.005|
Note: Patients may have had more than one reason for clinical worsening.
There was a significant delay in the time to clinical worsening for patients receiving Letairis compared to placebo. Results in subgroups such as the elderly were also favorable.
Figure 5 : Time to Clinical
Time from randomization to clinical worsening with Kaplan-Meier estimates of the proportions of failures in ARIES-1 and ARIES-2.
p-values shown are the log-rank comparisons of Letairis to placebo stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients
Long-term Treatment Of PAH
In long-term follow-up of patients who were treated with Letairis (2.5 mg, 5 mg, or 10 mg once daily) in the two pivotal studies and their open-label extension (N = 383), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 93%, 85%, and 79%, respectively. Of the patients who remained on Letairis for up to 3 years, the majority received no other treatment for PAH. These uncontrolled observations do not allow comparison with a group not given Letairis and cannot be used to determine the long-term effect of Letairis on mortality.
Adverse Effects In Idiopathic Pulmonary Fibrosis (IPF)
A randomized controlled study in patients with IPF, with or without pulmonary hypertension (WHO Group 3), compared Letairis (N = 329) to placebo (N = 163). The study was terminated after 34 weeks for lack of efficacy, and was found to demonstrate a greater risk of disease progression or death on Letairis. More patients taking Letairis died (8% vs. 4%), had a respiratory hospitalization (13% vs. 6%), and had a decrease in FVC/DLCO (17% vs. 12%) [see CONTRAINDICATIONS].
Last reviewed on RxList: 6/3/2014
This monograph has been modified to include the generic and brand name in many instances.
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