Brand Name: Letairis

Generic Name: Ambrisentan

Manufacturer: Gilead Sciences Inc

Drug Class: Endothelin-receptor antagonists

Uses: Treatment of pulmonary hypertension World Health Organization Group I patients with WHO Class II or III symptoms to improve exercise capacity and decrease the rate of clinical deterioriation

Mechanism of Action: Ambrisentan is a selective endothelin-A receptor antagonist.¹ Endothelin-1 is a potent autocrine and paracrine peptide produced primarily by vascular endothelial cells.¹  Endothelin-1  constricts blood vessels and this can result in increased mean right atrial pressure and cause more complications with the disease.¹ There are 2 receptor subtypes of endothelin: A and B. Endothelin A causes vasoconstriction and cell proliferation. Endothelin-B receptor causes dilation of blood vessels and increases the clearance of endothelin-1.¹ Ambrisentan is an antagonist for the endothelin-A receptor. Benefits of being selective for endothelin-A receptor include preventing constriction of the vessels in the pulmonary system and maintaining the benefits of Endothelin-B in patients.¹

Metabolism: Hepatic metabolism through CYP3A4, CYP2C19, uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S and 1A3S. Some in vitro studies also suggest metabolism via the organic anion transport system and P-glycoprotein^1,2

Elimination: Primarily by non-renal pathways; however, biliary contribution not characterized^1,2

Efficacy:

Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AK, Frost AE, Zwice D, Naeje R, Shapiro S, Olschewski H, Rubin LJ. Ambrisentan Therapy for Pulmonary Arterial Hypertension. Journal of the American College of Cardiology. 2005;46(3) 529-35.

Study design: The purpose of this 24 week study (12 week double blind phase followed by an 12 week open-label extension) was to examine the efficacy and safety of four different doses of ambrisentan in patients with pulmonary arterial hypertension.

Description of study: The primary efficacy endpoint was a change in exercise capacity, defined as the change from baseline in 6 minute walking distance. The secondary endpoints included a change from baseline at week 12 in the Borg dyspnea index, WHO functional class, quality of life assessed by a global assessment, and time to clinical worsening of pulmonary arterial hypertension.

Results: Sixty four patients were randomized to one of four ambrisentan groups (1, 2.5, 5, or 10 mg ambrisentan). Baseline characteristics of the groups were similar except for a shorter 6 minute walking distance in the 10 mg group, which might have indicated more severe disease in those patients.  The 6 minute walking distances(6MWD) improved for all dose groups combined after 12 weeks of therapy, with a mean increase from baseline of 36.1 meters (p value <.0001).  The improvements in exercise capacity were maintained up to 24 weeks for the respective groups: + 50.2 (p<.0001), + 50.9 (p<.0001), and + 54.2 meters (p<.0001) at 16, 20, and 24 weeks. By week 12, there was an improvement from baseline in the Borg dyspnea index score. Improvements were seen in WHO functional class for all dose groups, and no dose-response relationship was observed. 64% of the patients at baseline were WHO class III and the rest were WHO class II. At week 12, 38% of the patients were in WHO class III, 50% in WHO class II, and 12% were WHO class I.  Eighteen patients improved one or more WHO functional classes, and only 2 patients worsened at week 12. The most frequently reported side effects during the 12 week blinded period were peripheral edema (25%), nasal congestion (18.8%), upper respiratory infection (18.8%), headache (15.6%), flushing (12.5%), and nausea (12.5%).

Limitations: There was no comparison group to determine the relative efficacy of ambrisentan. Also, the patients randomized to the 5 or 10 mg groups initially received 2.5 mg, with the doses titrated upward over several weeks to the randomized dose. If the study duration was 12 weeks, they would have received their effective dose for less time.

Conclusion: Ambrisentan can improve exercise capacity, symptoms, and hemodynamic parameters in patients with pulmonary arterial hypertension. Ambrisentan has a small incidence and severity of serum aminotransferase abnormalities that do not appear to be dose dependent.  Since there was no control group, the comparative efficacy to other agents used to treat pulmonary hypertension is unknown.

ARIES-1: Oudiz RJ, Torres F, Frost AE, Badesch DB, Olschewski H, Galie N, McGoon MD,McLaughlin V, Rubin LJ.  A placeobo-controlled, efficacy and safety study of ambrisentan in patients with pulmonary arterial hypertension

Study objective: This study looked at the safety and efficacy of two doses of ambrisentan (5 and 10 mg) once daily compared to placebo.

Results: Two hundred and two patients were randomized to 1 of 3 treatment groups for the 12 week study duration. The primary endpoint, placebo adjusted change from baseline, in 6MWD was + 51.4m (p=.0001) for the 10 mg group and +30.6 m (p=.0084) for the 5 mg group. Significant improvements in the placebo-corrected 6MWD change from baseline to week 12 were seen with both dose groups (+ 31 m for 5 mg, p=.008; + 51 m for 10 mg; p<.001). There was an improvement in the Borg dyspnea index, although the time to clinical worsening did not significantly improve in the ambrisentan groups versus the placebo (p>.05). No patients experienced serum aminotransferase levels greater than three times the upper limit. No clinical changes were needed for patients on warfarin therapy.

Limitations: The article only reported the abstract with a brief summary of the objective, methods, results, and conclusion. Thus, many study details were not provided.

Conclusion: Ambrisentan resulted in improvement in the Borg dyspnea index and 6MWD in patients with PAH. More studies should be done to evaluate how this agent best fits into the management of pulmonary arterial hypertension.

Contraindications: Hypersensitivity to any component of ambrisentan. Ambrisentan is an FDA category risk factor X for pregnancy, and this drug is definitely contraindicated in women who become pregnant.² Teratogenicity is a known characteristic of the endothelin receptor antagonists as a class, and this can result in fetal harm if given to a pregnant women.¹ Pregnancy must be excluded before and during treatment (which includes one month after discontinuation of therapy) by the use of 2 reliable methods of contraception, which includes at least one form of primary contraception (tubal sterizilation , IUD, partner’s vasectomy, hormonal contraception).¹ Advise females of childbearing potential that if they notice any delay in the onset of menses or other reasons to suspect pregnancy, they should notify their primary care provider in order to obtain a pregnancy test.¹

Precautions: The two major warnings to watch for include hematological changes and hepatic impairment.

Hematological changes: A reduction in the hemoglobin/hematocrit can be seen within the first few weeks of therapy with the levels eventually stabilizing.² In some patients, there has been > 15% reduction in hemoglobin and hematocrit levels.² Measure hemoglobin prior to initiating therapy, at 1 month, and periodically thereafter.² If there are significant decreases in hemoglobin therapy with the absence of other causes, this may warrant therapy to be discontinued.²

 Hepatic impairment: avoid use in moderate-severe hepatic impairment.² This drug has been associated with a significant increase in transaminase (ALT or AST), with elevelations >3 times the upper limit of normal in up to 3% of treated patients.² These elevations of the transaminases are dose dependent and use of this agent should be avoided in patients who have elevated serum transaminases (> 3 times upper limit of normal) at baseline.² Bilirubin increases can also occur. Another component that can be increased is bilirubin.² Hepatic function should be monitored closely at least on a monthly basis for the duration of therapy.² The dose should be reduced or therapy be interrupted if the transaminases > 3 times upper limit of normal and less than or equal to 5 times upper limit of normal occur.² Patients who develop levels greater than 5 times the upper limit of normal and less than or equal to 8 times the upper limit of normal should discontinue therapy.² Treatment should be stopped in patients who develop elevated AST and ALT > 8 times the upper limit of normal and accompanied by symptoms of hepatic injury such as nausea, vomiting, abdominal pain, and fever or if the elevated serum bilirubin is greater than 2 times the upper limit of normal. ²

Adverse Reactions: Cardiovascular- peripheral edema (17%)²

                                  Central nervous system- headache (15%)²

                                  Cardiovascular- palpitation (5%) and flushing(4%)²

                                  Gastrointestinal: Constipation (4%), abdominal pain (3%)²

                                  Hematologic: Hemoglobin decreased (7%), hematocrit decreased

                                  Hepatic: Transaminases increased (ALT/AST: 1% to 3%)²

                      Respiratory: Nasal congestion (6%), dyspnea (4%), nasopharyngitis (3%),

                                  and sinusitis (3%)²

Drug Interactions:

• Caution should be used when administering the following CYP3A4 inhibitors to ambrisentan due to ambrisentan exposure and possibly increased adverse effects: nefazodone, itraconazole, ritonavir, ketoconazole, atazanavir, indinavir, nelfinavir, saquinavir, cyclosporine, clarithromycin, and telithromycin.³

• Rifampin- concurrent use of ambrisentan and rifampin can result in decreased ambrisentan concentration. Use caution if ambrisentan is coadministered with strong inducers of CYP450 isozymes, uridine 5-diphosphate glucuronosyltransferases(UGTs), and p-glycoprotein, such as rifampin, as this may lead to decreased ambrisentan exposure.³

• Omeprazole- use of ambrisentan and omeprazole together can result in increased ambrisentan exposure. Use caution if ambrisentan is coadministered with a strong CYP2C19 inhibitor, such as omeprazole, as this may lead to increased ambrisentan exposure.³

Dosing/Administration:

            Usual dose: Pulmonary arterial hypertensive disease WHO functional class II or III:

            Initially 5 mg once daily orally with or without food; can increase to 10 mg once daily if

            the 5 mg dose is tolerated; dosage adjustments can be made based on the monthly liver

            function tests.¹

Geriatric dose: the maximum dosage limit for the elderly population is 10 mg/day     orally.¹

            Pediatric dose: not established

            Renal impairment dose: Patients with a creatinine clearance of greater than 20 ml/min:

            No dosage adjustment is needed¹. CrCl < 20 ml/min: pharmacokinetic studies have not

            Been conducted and data for dosage adjustment are not available.¹

            Hepatic impairment dose: Patients with hepatic impairments

            Baseline aminotransferases- 3 times the upper limit of normal: Use not recommended.¹

            Baseline aminotransferases < 3 times ULN: No dosage adjustment necessary. Monitor

            liver function tests every month; reduce dose or interrupt treatment if increases do occur¹

            Elevation in aminotransferases > 3 and <= 5 times ULN during treatment: Repeat test to

            confirm. If the test is indeed confirmed, the daily dose should be decreased or treatment

            interrupted; specific dose reductions are not available from the manufacturer. Continue to

            monitor LFTs every 2 weeks until concentrations are < 3 times ULN. Letairis could then

            be introduced with more frequent monitoring of LFTs; recommendations on frequency

            are not available.¹

            Elevation in aminotransferases > 5 and <= 8 times ULN during treatment. Treatment

should be discontinued and monitor until the concentrations are < 3 times ULN. Ambrisentan can then be reintroduced with more frequent monitoring of LFTs; recommendations on frequency are not available.¹

            Elevation to aminotransferases >8 times ULN during treatment: Discontinue treatment

            permanently.¹

Conclusion: In conclusion, one can see that ambrisentan can improve exercise tolerance as well as the symptoms of pulmonary arterial hypertension. This agent can cause elevations of serum aminotransferase that do not seem to be dose dependent. Long-term studies of ambrisentan and comparative trials with other agents ultimately will determine the place of ambrisentan for the treatment of pulmonary arterial hypertension.

References used:

1. Letairis. Clinical Pharmacology[Internet database]. Gold Standard, Inc.,2007. Available at http://www.clinicalpharmacology.com. Accessed: October 24, 2007
2. Ambrisentan. Lexi-Drugs [database online]. Lexi-Comp, Inc; October 24, 2007
3. Ambrisentan. In: Drug Interactions [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically. Accessed October 24, 2007.
4. Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AK, Frost AE, Zwice D, Naeje R, Shapiro S, Olschewski H, Rubin LJ. Ambrisentan therapy for pulmonary arterial hypertension. JACC. 2005;46(3) 529-35.
5. Torres F. Systematic review of randomized, double-blind clinical trials of oral agents conducted in patients with pulmonary arterial hypertension. Int J of Clin Pract 2007;61(10) 1756-65.
6. Barst RJ. A Review of pulmonary arterial hypertension. Vasc Health Risk Manag 2007;3(1) 11-22.

Prepared by Doctor of Pharmacy Candidate, Ed Posti