Pharmacokinetic Study of Sub-q and IV Treprostinil in Kids With Pulmonary Arterial Hypertension (PAH) (PKRemodulin)

Multi-center, Open-label Pharmacokinetic Study of Subcutaneously and Intravenously Administered Treprostinil in Children With Pulmonary Arterial Hypertension (PAH)

Abstract

This is a multi-center, open-label pharmacokinetic (PK) study examining the relationship between the steady-state plasma concentration and dose of treprostinil delivered intravenously or subcutaneously in children with pulmonary arterial hypertension (PAH). Subjects will be divided into 5 cohorts by age. A blood sample will be obtained from each subject at steady state. Additional blood samples will be obtained from a small subset of subjects with a 15% increase or with at least a 15ng/kg/min increase in dose from steady state. Samples will be sent to a pharmacokinetic laboratory for analysis. Linear regression analysis will be used to determine the relationship between the steady state plasma concentration and drug dose. A power model will be used to assess dose proportionality.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension

Detailed Description

Background Information and Rationale

Treprostinil has not been adequately studied to determine its safety and efficacy in children ≤ 16 years old. However, the drug's use and tolerance in children with PAH has been demonstrated in studies with small sample sizes.

Although the pharmacokinetic relationship of treprostinil has been established in adult patients with PAH, the relationship between the steady-state plasma concentration and dose for children requires further investigation because of physiologic differences, such as the maturity of enzyme systems and drug clearance mechanisms, between children and adults. The subjects in this study will be divided into cohorts by age to address the physiologic changes that occur throughout childhood.

Currently, no data exists demonstrating the relationship between the steady-state plasma concentration and dose for children treated with intravenously or subcutaneously delivered treprostinil. Understanding the pharmacokinetics of treprostinil among different age cohorts in children will provide the data to make an informed recommendation for dosing based on age (and possibly weight).

• Study Type: Observational
• Enrollment (Actual): 51

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Lucille Packard Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Target enrollment for this study is a total of 50 pediatric patients among all participating sites with a goal of 65 total blood samples. Cohorts will be: 0-12 months; 1-3 years; 4-6 years; 7-11 years; 11-16 years. Each cohort will have 10 patients with 5 patients on a dose ≤ 50ng/kg/min and 5 patients on a dose ≥51-120ng/kg/min.

Description

Inclusion Criteria:

1. Patients must be on continuous intravenous or subcutaneous treprostinil for the treatment of pulmonary arterial hypertension, defined as mean pulmonary artery pressure >25mmHg at rest with a PVRi > 3 Wood units.
2. Patients must be between the ages of 0 to 16 years at the time of study enrollment.
3. Written informed consent and assent, when applicable, must be completed.

Exclusion Criteria:

1. Patients with severe liver or renal diseases.
2. Female patients who may be pregnant or breastfeeding
3. Written informed consent and assent not completed due to patient and/or parent or legal guardian unwilling to participate.
4. Patients on concomitant use of a CYP2C inhibitor or inducer.

Study Plan

How is the study designed?

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort
0 months - 1 year
11-16 years
7-11 years
4-6 years
1-3 years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the relationship between steady-state plasma concentration and dose of treprostinil within each age cohort and among age cohorts.	A blood sample will be obtained from each subject at steady state. Additional blood samples will be obtained from a small subset of subjects with a 15% increase or with at least a 15ng/kg/min increase in dose from steady state.	at least 48 hours after most-recent titration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To correlate PK level of treprostinil with the presence or absence of side effects	A survey of side effects (GI, neurological, cardiac, respiratory, skin) will be administered at time of blood draw.	At time of blood draw

Collaborators and Investigators

• Sponsor: Jeffrey A. Feinstein
• Collaborators: University of Colorado, Denver; Children's Hospital of Philadelphia; Seattle Children's Hospital; United Therapeutics

Publications and helpful links

General Publications

• Levy M, Celermajer DS, Bourges-Petit E, Del Cerro MJ, Bajolle F, Bonnet D. Add-on therapy with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. J Pediatr. 2011 Apr;158(4):584-8. doi: 10.1016/j.jpeds.2010.09.025. Epub 2010 Oct 30.
• Ivy DD, Claussen L, Doran A. Transition of stable pediatric patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil. Am J Cardiol. 2007 Mar 1;99(5):696-8. doi: 10.1016/j.amjcard.2006.09.119. Epub 2007 Jan 10.
• McSwain CS, Benza R, Shapiro S, Hill N, Schilz R, Elliott CG, Zwicke DL, Oudiz RJ, Staszewski JP, Arneson CP, Wade M, Zaccardelli D, McLaughlin V. Dose proportionality of treprostinil sodium administered by continuous subcutaneous and intravenous infusion. J Clin Pharmacol. 2008 Jan;48(1):19-25. doi: 10.1177/0091270007309708.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: January 9, 2014
• First Submitted That Met QC Criteria: December 11, 2014
• First Posted (Estimate): December 17, 2014

Study Record Updates

• Last Update Posted (Actual): October 5, 2017
• Last Update Submitted That Met QC Criteria: October 3, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: pulmonary arterial hypertension; remodulin; pharmacokinetic analysis; trepostinil
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: UT PK Treprostinil

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Publication