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Oral treprostinil in transition or as add-on therapy in pediatric pulmonary arterial hypertension.

ABSTRACT: Treprostinil, a prostacyclin analogue, is approved for the treatment of pulmonary arterial hypertension (PAH) in adults. Transition from parenteral to oral treprostinil has been successfully accomplished in adults with PAH but not in children. In this multicenter study, pediatric patients treated with parenteral (Cohort 1) or inhaled (Cohort 2) treprostinil were transitioned to oral treprostinil. Prostacyclin-naïve individuals on background oral PAH therapy received oral treprostinil as add-on therapy (Cohort 3). Successful transition was oral treprostinil dose maintenance through week 24. Patients were monitored for adverse events (AEs), 6-min walk distance (6MWD), PAH symptoms, World Health Organization (WHO) Functional Class (FC), cardiac magnetic resonance imaging (cMRI), cardiopulmonary exercise testing (CPET), and quality of life through 24 weeks. A total of 32 patients were enrolled in the study; 23 (72%) were girls (mean age?=?12.2 years). All patients were on background oral PAH therapy. Overall, patients (96.9%) maintained transition to oral treprostinil; one patient (Cohort 1) transitioned to oral treprostinil, then back to parenteral after experiencing syncope and WHO FC change from II to III. Cohorts 1, 2, and 3 received a final mean oral treprostinil dose of 5.6, 3.3, and 4.5?mg t.i.d., respectively. All cohorts had variable changes in 6MWD, cMRI, and CPET. Overall, 12 serious AEs were reported. All patients had drug-related AEs including headache (81%), diarrhea (69%), nausea (66%), vomiting (66%), and flushing (56%). Pediatric patients maintained transition to oral treprostinil with preservation of exercise capacity and WHO FC. Prostanoid-related AEs were most common and similar to those reported in adults.

SUBMITTER: Ivy DD

PROVIDER: S-EPMC6628532 | biostudies-literature | 2019 Jul-Sep

REPOSITORIES: biostudies-literature

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Oral treprostinil in transition or as add-on therapy in pediatric pulmonary arterial hypertension.

Ivy D Dunbar DD Feinstein Jeffrey A JA Yung Delphine D Mullen Mary P MP Kirkpatrick Edward C EC Hirsch Russel R Austin Eric D ED Fineman Jeffrey J Truong Uyen U Solum Derek D Deng C Q CQ Hopper Rachel K RK

Pulmonary circulation 20190701 3

Treprostinil, a prostacyclin analogue, is approved for the treatment of pulmonary arterial hypertension (PAH) in adults. Transition from parenteral to oral treprostinil has been successfully accomplished in adults with PAH but not in children. In this multicenter study, pediatric patients treated with parenteral (Cohort 1) or inhaled (Cohort 2) treprostinil were transitioned to oral treprostinil. Prostacyclin-naïve individuals on background oral PAH therapy received oral treprostinil as add-on t ...[more]

PMID: 31215336

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Project description:Background and aimsTreprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing.MethodsPatients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in CYP2C8, CYP2C9, and ABCC4. A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher's exact test was used for categorical data and Kruskal-Wallis test or Wilcoxon rank sum were used for continuous data.ResultsA total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in CYP2C8 (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in CYP2C9 (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for ABCC4 (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91; p = 0.04]. Genetic variants were not significantly associated with dosing.ConclusionGenetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing was not associated with genetic variants in metabolizing enzymes for treprostinil. Our findings suggest significant variability in treatment persistence to oral treprostinil, with pharmacogenomics being a potentially important contributor.The reviews of this paper are available via the supplemental material section.

Dataset Information

Oral treprostinil in transition or as add-on therapy in pediatric pulmonary arterial hypertension.

Publications

Oral treprostinil in transition or as add-on therapy in pediatric pulmonary arterial hypertension.

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