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Treatment-related biomarkers in pulmonary hypertension patients on oral therapies.

ABSTRACT: BACKGROUND:Multiple classes of oral therapy are available for the treatment of pulmonary arterial hypertension (PAH), but there is little to guide clinicians in choosing a specific regimen or therapeutic class. We aimed to investigate whether treatment-relevant blood biomarkers can predict therapy response in prevalent PAH patients. METHODS:This prospective cohort study longitudinally assessed biomarkers along the endothelin-1 (ET-1) and nitric oxide (cGMP, ADMA, SDMA, nitrite, and S-nitrosohemoglobin) pathways along with the cGMP/NT-proBNP ratio over 12 months in patients with WHO Group 1 PAH on oral PAH-specific therapies. The relationship between biomarkers and 6MWD at the same and future visits was examined using mixed linear regression models adjusted for age. As cGMP can be elevated when NT-proBNP is elevated, we also tested the relationship between 6MWD and the cGMP/NT-pro BNP ratio. Patients with PAH with concomitant heart or lung disease or chronic thromboembolic pulmonary hypertension (CTEPH) were included in a sensitivity analysis. RESULTS:The study cohort included 58 patients with PAH treated with either an endothelin receptor antagonist (27.6%), phosphodiesterase-5 inhibitor (25.9%) or a combination of the two (43.1%). Among biomarkers along the current therapeutic pathways, ET-1 and the cGMP/NT-proBNP ratio associated with same visit 6MWD (p?=?0.02 and p?=?0.03 respectively), and ET-1 predicted future 6MWD (p?=?0.02). ET-1 (p?=?0.01) and cGMP/NT-proBNP ratio (p?=?0.04) also predicted future 6MWD in the larger cohort (n?=?108) of PAH patients with concomitant left heart disease (n?=?17), lung disease (n?=?20), or CTEPH (n?=?13). Finally, in the larger cohort, SDMA associated with 6MWD at the same visit (p?=?0.01) in all subgroups and ADMA associated with 6MWD in PAH patients with concomitant lung disease (p?=?0.03) and PAH patients on ERA therapy (p?=?0.01). CONCLUSIONS:ET-1, cGMP/NTproBNP ratio, and dimethylarginines ADMA and SDMA are mediators along pathways targeted by oral PAH therapies that associate with or predict 6MWD.

SUBMITTER: Swaminathan AC

PROVIDER: S-EPMC7678114 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Treatment-related biomarkers in pulmonary hypertension patients on oral therapies.

Swaminathan Aparna C AC Zhu Hongmei H Tapson Victor V Lokhnygina Yuliya Y Poms Abby A Kelleher Zach Z Gaspard Elijah E Kennedy Karla K Fee Brian E BE Fortin Terry T Mason S Nicholas SN Parikh Kishan K McMahon Tim J TJ

Respiratory research 20201119 1

<h4>Background</h4>Multiple classes of oral therapy are available for the treatment of pulmonary arterial hypertension (PAH), but there is little to guide clinicians in choosing a specific regimen or therapeutic class. We aimed to investigate whether treatment-relevant blood biomarkers can predict therapy response in prevalent PAH patients.<h4>Methods</h4>This prospective cohort study longitudinally assessed biomarkers along the endothelin-1 (ET-1) and nitric oxide (cGMP, ADMA, SDMA, nitrite, an ...[more]

PMID: 33213478

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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.

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Treatment-related biomarkers in pulmonary hypertension patients on oral therapies.

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Treatment-related biomarkers in pulmonary hypertension patients on oral therapies.

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