Clinical trial NCT02318186: Pharmacokinetic Study of Sub-q and IV Treprostinil in Kids With Pulmonary Arterial Hypertension (PAH)
Official title: Multi-center, Open-label Pharmacokinetic Study of Subcutaneously and Intravenously Administered Treprostinil in Children With Pulmonary Arterial Hypertension (PAH)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pulmonary Arterial Hypertension
Keywords: pharmacokinetic analysis
remodulin
trepostinil
pulmonary arterial hypertension
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: United Therapeutics
name: Seattle Children's Hospital
name: University of Colorado, Denver
name: Children's Hospital of Philadelphia
First posted: 2014-12-17
Enrollment: 51
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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.

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).

Eligibility criteria: 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.

Primary outcomes:
measure: To determine the relationship between steady-state plasma concentration and dose of treprostinil within each age cohort and among age cohorts.
timeFrame: at least 48 hours after most-recent titration
Secondary outcomes:
measure: To correlate PK level of treprostinil with the presence or absence of side effects
timeFrame: At time of blood draw
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucille Packard Children's Hospital
state: California
Study officials:
affiliation: Stanford University
name: Jeffrey Feinstein, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.