Pediatric Pulmonology 48:27–34 (2013)
Clinical Safety, Pharmacokinetics, and Efficacy of Ambrisentan Therapy in Children With Pulmonary Arterial Hypertension Shinichi Takatsuki, MD,1* Erika B. Rosenzweig, MD,2 Warren Zuckerman, MD,2 Daniela Brady, RN,2 Michelle Calderbank, RN,1 and D. Dunbar Ivy, MD1 Summary. Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 18 vs. 45 20 mmHg, n ¼ 13, P ¼ 0.04, add-on; 52 17 vs. 45 19 mmHg, n ¼ 13, P ¼ 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4–44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 452 ng/ml, mean time to peak plasma concentration was 3.2 2.1 hours, and mean area under the curve plasma concentration was 6657 4246 nghour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children. Pediatr Pulmonol. 2013; 48:27–34. ß 2012 Wiley Periodicals, Inc. Key words: endothelin receptor antagonists; safety; tolerability; Organization.
World Health
Funding source: Jayden DeLuca Foundation; Leah Bult Foundation; UL1 RR025780, Colorado Clinical Translational Science Institute, National Center for Research Resources, National Institutes of Health.
1 Pediatric Cardiology, University of Colorado School of Medicine, Children’s Hospital, Aurora, Colorado.
support from Gilead as well as honoraria for consulting. Dr Zuckerman has received grant support from Gilead.
2
*Correspondence to: Shinichi Takatsuki, MD, Pediatric Cardiology, The Children’s Hospital, University of Colorado Denver School of Medicine, 13123 East 16th Avenue, B100, Aurora, CO 80045. E-mail:
[email protected]
Pediatric Cardiology, Columbia University College of Physicians and Surgeons, New York, New York. Conflicts of interest: The ambrisentan PK study was founded by an investigator initiated grant to Dr. Ivy by Gilead. PK data was evaluated at the University of Colorado. Disclosures: Dr Ivy serves as a member of the Gilead Sciences Research Scholars Program. The University of Colorado School of Medicine receives consultant fees from Actelion, Gilead, Pfizer, and United Therapeutics for Dr Ivy to be consultant. Dr Rosenzweig has received grant
ß 2012 Wiley Periodicals, Inc.
Received 28 September 2011; Accepted 19 January 2012. DOI 10.1002/ppul.22555 Published online 17 April 2012 in Wiley Online Library (wileyonlinelibrary.com).
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Takatsuki et al.
INTRODUCTION
Endothelin-1 (ET-1) was initially isolated from endothelial cell cultures in 1988 by Yanagisawa.1 Since the discovery of ET-1, over-expression of ET-1 has been demonstrated in patients with pulmonary arterial hypertension (PAH).2–6 ET-1 is a potent vasoconstrictor and is mediated by two types of endothelin receptors including type A and type B. The Food and Drug Administration (FDA) has approved two endothelin receptor antagonists (ERA), bosentan and ambrisentan, in adults with PAH. Ambrisentan differs from bosentan as it is highly selective for the endothelin type A receptor whereas bosentan is a dual antagonist. Ambrisentan is indicated for once-daily treatment of PAH to improve exercise capacity and delay clinical worsening in adults with World Health Organization (WHO) functional class II or III symptoms.7–10 The two pivotal trials of ambrisentan in PAH were randomized, double-blind, placebo-controlled, multicenter, and efficacy studies (ARIES) in adults with idiopathic PAH or PAH associated with connective tissue disease, anorexigen use, or HIV infection.11 The ARIES trials demonstrated the efficacy and safety of ambrisentan through improvements in exercise tolerance, WHO functional class, and Borg dyspnea score with good safety and tolerability. The safety concerns of endothelin receptor antagonists are mainly related to hepatotoxicity, decreasing hemoglobin level, and teratogenicity.7 In the treatment of PAH patients, ambrisentan is associated with a lower incidence of liver function test abnormalities compared to bosentan.11–14 Recently, FDA removed the black box warning for liver function tests in the ambrisentan label. However, in children with PAH, the safety, pharmacokinetics and clinical efficacy of ambrisentan therapy have not been well studied. Our aim was to investigate the pharmacokinetics, clinical safety, tolerability, and efficacy of ambrisentan therapy in children with PAH after transition from bosentan and in those receiving ambrisentan as add-on therapy. METHODS Study Population and Outcome Measures
This retrospective cohort study was performed using clinical data from pediatric patients with PAH receiving commercially available ambrisentan. All patients were enrolled in an IRB approved protocol for patient follow-up and treated with ambrisentan from July 2007 to September 2011 at Children’s Hospital Colorado, Denver and Columbia University Medical Center, New York. The clinical impact of ambrisentan was evaluated by WHO functional class, plasma brain natriuretic peptide, and catheterization at baseline and follow-up Pediatric Pulmonology
after administration of ambrisentan in a subset of patients. By right heart catheterization using a flow directed Swan-Ganz catheter and a systemic arterial line for monitoring, we measured mean right atrial pressure, mean pulmonary artery pressure, mean systemic blood pressure, and pulmonary capillary wedge pressure. Accordingly, we calculated pulmonary vascular resistance index and pulmonary vascular resistance/systemic vascular resistance ratio. Cardiac output was obtained using thermo-dilution and cardiac index was calculated. If a significant intra-cardiac defect remained, cardiac output was obtained by the Fick method using the LaFarge estimation. Plasma brain natriuretic peptide (BNP) was assayed on an i-STAT1 system using the two-site enzyme-linked immunosorbant assay (Abbott Laboratories, IL). A cutoff of 100 pg/ml was chosen as the cutoff for BNP level as it is the upper normal value in our laboratory. Side effects, laboratory evaluations, including monthly liver function tests, pregnancy tests in girls of childbearing potential, and clinical worsening were used to assess safety and tolerability. Side effects such as headache, flushing, myalgia, peripheral edema, nasal congestion, and abnormalities of liver function tests were monitored at each clinic visit at 3 months intervals. Liver function tests including aspartate aminotransferase, alanine aminotransferase, and total bilirubin were assessed monthly. Aminotransferase abnormalities were defined as elevation of concentrations over 2 the upper limit of normal resulting in dose reduction or eventual discontinuation of ambrisentan. Clinical worsening which included the initiation of additional PAH medications, hospitalization due to deterioration of PAH symptoms, septostomy, and death due to heart failure were determined. Other clinical variables included evaluation for chest pain, syncope, nausea, dyspnea with exercise, and reason for discontinuation of ambrisentan. One patient was previously described in a manuscript of ambrisentan in Eisenmenger syndrome.8 The pharmacokinetic (PK) evaluation was an openlabel, non-controlled, multiple-dose study in patients receiving ambrisentan for at least 30 days. Blood samples for ambrisentan PK assessments were collected at pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, and 12 h post-dose. We analyzed peak plasma concentration (Cmax) and time to Cmax (Tmax) from the concentration data. In addition, we calculated the area under the plasma concentration–time curve during a dose interval (AUC) and the AUC from time 0 to infinity, AUC (0-tau). Statistical Methods
All analyses included patients with baseline and at least one post-baseline measure. At baseline and after
Ambrisentan in Pediatric Pulmonary Hypertension
start of treatment, clinical data was abstracted. In a patient on ambrisentan where treatment was terminated due to worsening of the disease, the clinical data were obtained and the last observation was used for analysis. The missing values for all measurements were excluded from the analysis. All results are reported as median and range or mean standard deviation along with the 95% confidence interval as appropriate. Comparisons of natriuretic peptide levels and hemodynamic variables between baseline and after initiation of ambrisentan were performed using Student t-tests, or MannWhitney’s U-test as appropriate. For longitudinal data, analysis was performed with repeated measures. The level of statistical significance was defined as P-value of 0.05. Analyses were conducted using Statmate III for Windows (Atoms Co., Tokyo, Japan).
RESULTS Demographic Data
A total of 38 pediatric patients with PAH received ambrisentan during the observational period. The median (range) and mean ( standard deviation) age was 11 years old (2–18 years old) and 10.1 4.1 years old with 50% being female. The etiologies of PAH included idiopathic PAH (n ¼ 19), PAH associated with congenital heart disease (n ¼ 15), PAH associated with connective tissue disease (n ¼ 1), and others (n ¼ 3; heritable, pulmonary capillaritis, and bronchopulmonary dysplasia). Among patients with congenital heart disease, six patients underwent cardiac surgery before initiation of ambrisentan therapy. The remaining nine patients with unrepaired congenital heart disease had atrial septal defect (n ¼ 2), ventricular septal defect (n ¼ 2), patent ductus arteriosus (n ¼ 2), atrioventricular septal defect (n ¼ 1), aortopulmonary window (n ¼ 1), and isolated pulmonary artery of ductal origin (n ¼ 1). Among these patients, eight patients were classified as Eisenmenger syndrome due to mild to moderate desaturation. The baseline concomitant vasodilator therapies included infusion of treprostinil or epoprostenol, iloprost, sildenafil, and tadalafil. Thirty-three patients (87%) received a phosphodiesterase type 5 inhibitor and ambrisentan as combination therapy (Table 1).
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TABLE 1— Clinical Characteristics at Baseline
All Total number 38 Age (year-old) Median (range) 11 (2–18) Mean standard deviation 10.1 4.1 Gender (male/female) 19/19 Pathogenesis (number) Idiopathic 19 Congenital heart disease 15 Connective tissue disease 1 Others 3 Race (number) White 28 Hispanic 5 Black 5 Concomitant therapy (number) 17 Treprostinil1 Epoprostenol 6 Iloprost 3 Sildenafil 28 Tadalafil 5 WHO functional class (number) Class I 6 Class II 21 Class III 6 Class IV 2
Transition (on bosentan)
Add-on
15
23
9 (6–17) 10.3 3.6 8/7
11 (2–18) 10.0 4.5 11/12
10 3 1 0
9 12 0 3
8 4 3
20 1 2
5 3 2 11 1
12 3 1 17 4
6 5 3 1
0 16 3 1
1
Intravenous, subcutaneous, or inhaled.
Ambrisentan Dose
Eleven patients started 2.5 mg of ambrisentan as an initial dose while the remaining 27 patients started 5 mg. In patients who were greater than 40 kg, the initial ambrisentan dose was 5 mg and patients who were
