What published dosing exists for ambrisentan for pulmonary arterial hypertension in pediatric patients?

Comment by InpharmD Researcher

According to the American Heart Association and American Thoracic Society guidelines, ambrisentan is recommended at a dose range of 5-10 mg daily to treat children with pulmonary arterial hypertension (PAH). While there is limited data available that evaluates safe and effective dosing of ambrisentan for treatment of PAH in pediatric patients, weight-based doses up to 10 mg have been observed to be well tolerated and potentially therapeutic in retrospective studies. Expert opinion also suggests ambrisentan can be administered according to a weight-based dosing strategy (see Table 3).
Background

According to 2015 guidelines from the American Heart Association and American Thoracic Society, treatment of pulmonary arterial hypertension (PAH) in pediatrics is generally based on experience and small observational studies. While using oral ambrisentan at a dose range of 5-10 mg daily is suggested as a possible therapeutic approach to treat children with PAH, utilizing ambrisentan in pediatric patients aged <5 years has not been studied. [1]

A 2021 review discusses possible therapeutic options for PAH in children including ambrisentan. Given the limited data available evaluating ambrisentan in pediatrics with PAH, ambrisentan is commonly administered off-label according to a weight-based dosing strategy (Table 3). One retrospective study (See Table 1) suggested that ambrisentan may have a favorable safety profile as well as potential efficacy in children; however, its dose-normalized exposure was shown to be highly variable. Given the various etiologies of PAH in children, there is no consensus on a preferred initial therapy (mono-therapy versus combination therapy); quality controlled studies with robust data on PAH therapy in a pediatric population are warranted. [2]

Another 2019 review detailed available therapeutic options to treat PAH in children. While ambrisentan has been shown to significantly improve performance on the 6-minute walk test when compared to placebo in adults patients, the drawback for its use in children is that compounding the oral suspension may not be feasible, given its hydrophobic nature; hence, its use in older children may be preferred. An ambrisentan dose of 2.5-5 mg ambrisentan is suggested to be used for children <20 kg. For children weighing > 20 kg, a dose of 5-10 mg daily is recommended. Given the lack of rigorous, randomized, controlled trials evaluating therapeutic options to treat PAH in children, understanding the mechanism of action and potential risk versus benefit as well as safety profile of the medication while choosing the optimal dosing seems to be critical. [3]

References:

[1] Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015;132:2037-2099. doi:10.1161/CIR.0000000000000329
[2] Gorenflo M, Ziesenitz VC. Treatment of pulmonary arterial hypertension in children. Cardiovasc Diagn Ther. 2021;11(4):1144-1159. doi:10.21037/cdt-20-912
[3] Ezekian JE, Hill KD. Management of Pulmonary Arterial Hypertension in the Pediatric Patient. Curr Cardiol Rep. 2019;21(12):162. Published 2019 Nov 28. doi:10.1007/s11886-019-1229-2
Relevant Prescribing Information

Pediatric Use:
Safety and effectiveness of ambrisentan tablets in pediatric patients have not been established. [4]

References:

[4] Ambrisentan [prescribing information]. Apotex Corp.; 2022.
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What published dosing exists for ambrisentan for pulmonary arterial hypertension in pediatric patients?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

 

Clinical Safety, Pharmacokinetics, and Efficacy of Ambrisentan Therapy in Children with Pulmonary Arterial Hypertension

Design

Multicenter, retrospective, observational, cohort study

N= 38

Objective

To investigate the pharmacokinetics, clinical safety, tolerability, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension (PAH) after transitioning from bosentan and in those receiving ambrisentan as add-on therapy

Study Groups

Transition from bosentan to ambristentan (n= 15)

Add-on ambristentan (n= 23)

Inclusion Criteria

Pediatric patients with PAH, receiving commercially available ambrisentan

Exclusion Criteria

Not disclosed

Methods

This trial was performed using pediatric clinical data from sites in Colorado and New York. Monitoring via Swan-Ganz catheter and systemic arterial line included mean right atrial, pulmonary artery, systemic blood, and pulmonary capillary wedge pressure. 

Patients weighing >40 kg received ambrisentan 5 mg as the initial dose (n=11) whereas patients weighing <20 kg received 2.5 mg as the initial dose (n= 27). Ten of the 27 patients who received 5 mg were up-titrated to 10 mg whereas all patients who received 2.5 mg were up-titrated to 5 mg. 

Duration

Treatment period: July 2007 through September 2011

Outcome Measures

Plasma brain natriuretic peptide; mean right atrial pressure; mean pulmonary artery pressure; pulmonary vascular resistance index; pulmonary/systemic vascular index ratio; cardiac output; clinical worsening

Baseline Characteristics

  

Transition (n= 15)

Add-on (n= 23)

  

Age, years

Median (range)

Mean ± SD

 

9 (6 to 17)

10.3 ± 3.6

 

11 (2 to 18)

10.0 ± 4.5

  

Female

7 (47%) 12 (52%)  

White

 8 (53%) 20 (87%)  

Pathogenesis

Idiopathic

Congenital heart disease

Connective tissue disease

Other

 

10 (67%)

3 (20%)

1 (7%)

0 (0%)

 

9 (39%)

12 (52%)

0 (0%)

3 (13%)

  

Concomitant therapy

Treprostinil

Epoprostenol

Iloprost

Sildenafil

Tadalafil

 

5 (33%)

3 (20%)

2 (13%)

11 (73%)

1 (7%)

 

12 (52%)

3 (13%)

1 (4%)

17 (74%)

4 (17%)

  

WHO functional class

Class I

Class II

Class III

Class IV

 

6 (40%)

5 (33%)

3 (30%)

1 (7%)

 

0 (0%)

16 (70%)

3 (13%)

1 (4%)

  
SD: standard deviation; WHO: World Health Organization  

Results

Endpoint

Transition (n= 15)*

Add-on (n= 23)**

p-value

Bosentan

 Ambrisentan

Before

 After  

Clinical variable

BNP, pg/mL

MRAP, mmHg

MPAP, mmHg

PVRI, unit x m2

P/SVIR

CI, L/min/m2

 

49 ± 34

74

55 ± 18

10.1 ± 5.6

0.8 ± 0.3

4.8 ± 1.4

 

72 ± 47

73

45 ± 20

9.3 ± 5.9

0.6 ± 0.4

4.0 ± 1.2

 

81 ± 105

63

52 ± 17

11.3 ± 6.0

0.9 ± 0.8

4.5 ± 1.2 

 

53 ± 41

72

45 ± 19

10.6 ± 8.7

0.8 ± 0.9

4.5 ± 1.5

 

NS

NS

0.04* vs 0.03**

NS

NS

NS 

Clinical worsening

Hospitalization due to HF

Septostomy

Initiation of other PAH drugs

Death

 

1 (7%)

1 (7%)

0 (0%)

0 (0%)

 

2 (9%)

0 (0%)

3 (13%)

0 (0%)

    

BNP: brain natriuretic peptide; MRAP: mean right atrial pressure; MPAP: mean pulmonary artery pressure; PVRI: pulmonary vascular resistance index; P/SVIR: pulmonary/systemic vascular index ratio; CI: cardiac index; HF: heart failure; PAH: pulmonary arterial hypertension; NS: not significant

Adverse Events

Common Adverse Events: nasal congestion (20% vs 26%), headache (7% vs 9%), flushing (0 vs 4%)

Percentage that Discontinued due to Adverse Events: five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. 

Study Author Conclusions

This study demonstrates the favorable clinical safety and potential efficacy of ambrisentan therapy in pediatric patients with PAH. In the present study, doses of 5 or 10 mg might be considered therapeutic in children, as the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in children were similar to those in adults after exposure to 5 to 10 mg dose which showed clinical improvement.

InpharmD Researcher Critique

In addition to limitations inherent to retrospective and observational design, no protocol was followed regarding the optimal dose titration of ambrisentan. Future controlled and larger trials are warranted to assess the appropriate dose and pharmacokinetic properties of ambrisentan. 



References:

Takatsuki S, Rosenzweig EB, Zuckerman W, Brady D, Calderbank M, Ivy DD. Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension. Pediatr Pulmonol. 2013;48(1):27-34. doi:10.1002/ppul.22555

 

A Randomized Study of Safety and Efficacy of Two Doses of Ambrisentan to Treat Pulmonary Arterial Hypertension in Pediatric Patients Aged 8 Years up to 18 Years

Design

Randomized, open-label, phase IIb 

N= 41

Objective

To assess the safety and efficacy of the endothelin receptor antagonist ambrisentan in pediatric pulmonary arterial hypertension (PAH)

Study Groups

Low dose (n= 21)

High dose (n= 20)

Inclusion Criteria

Aged 8 to ≤ 18 years; current diagnosis of PAH with symptom; meets hemodynamic criteria; treatment-naive; discontinued treatment with another endothelin receptor antagonist (ERA; eg, bosentan) ≥1 month previously because of elevated LFTs, or have been on a stable dose of drug therapy for PAH (eg, sildenafil or prostacyclin) for ≥1 months before the screening visit; consistent PAH treatment if applicable 

Exclusion Criteria

Taking an ERA, cyclosporin A; body weight < 20 kg; diagnosis of active hepatitis or clinically significant hepatic enzyme elevation; severe renal impairment (CrCl < 30 mL/min); history of not tolerating PAH therapy due to adverse effects; clinically significant fluid retention and/or anemia

Methods

Eligible patients were randomized to receive 2.5 or 5 mg ambrisentan based on their body weight to determine if a dose increase was appropriate. While the low-dose group remained on the baseline dose, the high-dose group was up-titrated to 5, 7.5, or 10 mg ambrisentan starting week 2 if deemed appropriate.

Duration

Treatment period: 24 weeks

Follow-up: 4-6 weeks

Outcome Measures

Primary: treatment-emergent adverse events (TEAEs)

Secondary: 6-minute walking distance (6MWD), change in World Health Organization (WHO) category

Baseline Characteristics

  

Low dose (n= 21)

High dose (n= 20)

Median age, years

8-11

12 to < 18

13 (8 to 16)

7 (33%)

14 (67%)

12 (8 to 16)

7 (35%)

13 (65%)

Female

 12 (57%) 15 (75%) 

Ethnicity

Hispanic/Latino

Not Hispanic/Latino

 

5 (24%)

16 (76%)

 

8 (40%)

12 (60%) 

Etiology of PAH

Idiopathic

Non-idiopathic

 

13 (62%)

8 (38%)

 

14 (70%)

6 (30%)

Median weight, kg

 36 (20.9 to 67) 38.1 (20.1 to 77)

WHO Functional Class

Class II

Class III

6MWD, median

 

18 (86%)

3 (14%)

453 (168 to 600)

 

14 (70%)

6 (30%)

420 (160 to 593)

Results

Endpoint

Low dose (n= 21)

High dose (n= 20)

TEAEs

Treatment-related

17 (81%)

8 (38%)

16 (80%) 

7 (35%)

Patients with adverse event of special interest

 6 (29%) 3 (15%)

WHO category

Improved

No change

 

6 (32%)

12 (63%)

 

4 (22%)

14 (78%)

6MWD ≥ 20-m increase

Week 12

Week 24

 

13 (62%)

14 (67%) 

 

11 (55%)

10 (50%)

Adverse Events

Common adverse events: headache (19% vs. 30%), nausea (19% vs. 15%), abdominal pain (19% vs. 5%), nasopharyngitis (14% vs. 10%), upper respiratory tract infection (14% vs. 5%)

Serious adverse events: the incidence was higher in the low-dose group (pharyngitis, pneumonia, general physical health deterioration, syncope, device breakage, and pulmonary hypertension) vs. the high-dose group  (device-related infection, acute cardiac failure, and right ventricular failure) where each category had 1 patient experiencing these events. 

Study Author Conclusions

Ambrisentan was well tolerated; TEAEs were consistent with the adult safety profile. Efficacy was similar to previous findings in adult PAH; Findings support a potentially similar benefit:risk profile in pediatric (8 to <18 years) and adult patients with PAH.

InpharmD Researcher Critique

This phase IIb study lacked a placebo group for a true comparison in doses. Moreover, the small sample size limits the interpretation and generalizability of the findings. The potential risk for children aged 0-3 years limited the patient inclusion criteria to children 8 years or older.



References:

Ivy D, Beghetti M, Juaneda-Simian E, et al. A randomized study of safety and efficacy of two doses of ambrisentan to treat pulmonary arterial hypertension in pediatric patients aged 8 years up to 18 years. The Journal of Pediatrics: X. 2020;5:100055.

 

Ambrisentan weight-based dosages in pediatric pulmonary arterial hypertension

Recommended dose

Maximum dose

 Approved age

0.1–0.2 mg/kg daily (simulated)

 5–10 mg daily (adult dose)  Off label use 

Body weight

< 20 kg: 1.5–2.5 mg daily

20–40 kg: 2.5–5 mg daily

> 40 kg: 5–10 mg daily (adult dose)
References:

Adapted from:
Gorenflo M, Ziesenitz VC. Treatment of pulmonary arterial hypertension in children. Cardiovasc Diagn Ther. 2021;11(4):1144-1159. doi:10.21037/cdt-20-912