Subcutaneous and Intravenous Treprostinil Pharmacokinetics in Children With Pulmonary Vascular Disease

Abstract

This study evaluated the pharmacokinetics of intravenous (IV) and subcutaneous (SC) treprostinil in pediatric patients with pulmonary vascular disease, and compared them with existing adult data from a similar cohort. Blood samples were collected from pediatric patients receiving steady-state IV or SC treprostinil and were assessed for plasma treprostinil concentration using liquid chromatography and tandem mass spectrometry. Forty participants, 15 receiving IV and 25 receiving SC treprostinil, were included in the analysis. Age ranged from 0.1 to 15.6 years. The median dose of treprostinil was 45.5 ng·kg−1·min−1 with a range of 8–146 ng·kg−1·min−1. There was a linear relationship between treprostinil dose and plasma concentration with an R 2 of 0.57. On average, there were higher blood concentrations per given dose of IV treprostinil compared with those per given dose of SC, but the difference was not significant. Compared with adult data, the slope of the pediatric data was similar, but the y-intercept was significantly lower. Additionally, the concentration per dose ratio was significantly higher in adults compared with children. Pediatric patients have significantly lower average blood concentrations of treprostinil per given dose compared with adults, and higher, but not significantly so, blood concentrations when treprostinil is administered IV as compared with SC administration.

Treprostinil Attains Clinically Therapeutic Concentrations in Neonates with Pulmonary Hypertension on Extracorporeal Membrane Oxygenation Support

“…With a half‐life of 2–4 hours in human adults, subcutaneous and intravenous treprostinil infusions reach steady‐state concentrations (Css) within 10–24 hours 19,20 . The relationship between the dose and Css is linear in doses up to 125.0 ng/kg/min 21 and in a pediatric population is best described by the following equation 13 :…”

“…The lower concentration of 0.99 ng/ml in patient II, may have been sampled in the midst of dose‐escalation (Figure 1) and before attaining Css after only two days of treprostinil infusion. The lower concentration may also be explained by the findings of Hall and colleagues, that within their pediatric study population, the younger the age, the lower the concentrations per dose were, implying proportional (/kg) faster metabolization and/or elimination of treprostinil in infants 13 . In an effort to negate the impact of circadian variation (20–30% difference between peaks and troughs), samples were collected at similar times during the day.…”

“…Collected plasma was stored at −80°C and subsequently shipped for concentration analysis with highperformance liquid chromatography in tandem with mass-spectrometry (AB/MDS Sciex API-5000; AB Sciex Pte Ltd., Singapore, Singapore) at a bio-analytics facility (Covance Inc., Madison, WI, USA) as detailed elsewhere. 13 Samples were analyzed in one batch using a validated assay with a lower limit of quantification of 10 pg/ml. Calibration standards, prepared in plasma from 0.010 to 5.00 ng/ml, were used to construct standard curves for treprostinil.…”

“…The lower concentration may also be explained by the findings of Hall and colleagues, that within their pediatric study population, the younger the age, the lower the concentrations per dose were, implying proportional (/kg) faster metabolization and/or elimination of treprostinil in infants. 13 In an effort to negate the impact of circadian variation (20-30% difference between peaks and troughs), samples were collected at similar times during the day. Considering the low number of patients, however, this study remains at risk for undue influence by interindividual variability (previously described as 14-26%).…”

Opportunities and challenges of pharmacotherapy for pulmonary arterial hypertension in children

“…More recently, however, Hall et al found that pediatric PAH patients receiving SQ treprostinil had lower plasma concentrations compared to the IV route, although this difference was not statistically significant. Additionally, they found that children eliminate treprostinil faster, as indicated by a significantly lower concentration to dose ratio compared to adults 54 …”