Pharmacokinetics of Oral Treprostinil in Children with Pulmonary Arterial Hypertension.

: As part of a clinical trial, this study examined the pharmacokinetics (PK) of oral treprostinil in children with pulmonary arterial hypertension (PAH). The trial consisted of 3 cohorts: transition from parenteral (Cohort 1) or inhaled (Cohort 2) treprostinil, or de novo addition (Cohort 3). Oral treprostinil was dosed 3 times daily (TID). PK samples were obtained prior to an oral treprostinil dose, and at 2, 4, 6 and 8 hours thereafter. The PK parameters were calculated using noncompartmental analysis. Thirty-two children (n=10 in Cohorts 1 and 2, n=12 in Cohort 3) were enrolled; median age was 12 years (range 7 to 17 years) and median weight was 42.2 kg (range 19.3 to 78 kg). Median oral treprostinil dose for all subjects was 3.8 mg (5.9, 3.5, and 4.0 mg for Cohorts 1, 2, and 3, respectively). The treprostinil concentration vs. time profile demonstrated a peak concentration at a median of 3.8 hours with wide variability. In Cohort 1, oral dosing led to higher peak (5.9 ng/mL) and lower trough (1 ng/mL) concentrations compared with parenteral (peak 5.4, trough 4.2 ng/mL), but a lower mean concentration (3.61 vs. 4.46 ng/mL), likely due to variable metabolism and noncomparable dosing. Both the area under the curve and average concentration were linearly correlated to oral treprostinil dose and dose normalized to body weight, but not weight or age alone. In pediatric patients, increased oral treprostinil dose or dose frequency may be required to minimize PK variability and achieve greater correlation with parenteral dosing.