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.

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).

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.

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.

Publication