EXPRESS: Long term study of oral treprostinil to treat pulmonary arterial hypertension: dosing, tolerability, and pharmacokinetics.
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SUBMITTER: White RJ
PROVIDER: S-EPMC7731723 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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EXPRESS: Long term study of oral treprostinil to treat pulmonary arterial hypertension: dosing, tolerability, and pharmacokinetics.
White R James RJ Parikh Keyur K Allen Roblee R Feldman Jeremy J Jerjez-Sanchez Carlos C Pan Lei L Keogh Ann M AM Vizza Carmine Dario CD Shapiro Shelly M SM Gordon Kathryn K Broderick Meredith M Bartolome Sonja S
Pulmonary circulation 20190710
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Project description:Oral treprostinil has been shown to improve exercise capacity and delay disease progression in patients with pulmonary arterial hypertension (PAH), but its effects on hemodynamics are not well-characterized. The FREEDOM-EV trial was a Phase III, international, placebo-controlled, double-blind, event-driven study in 690 participants with PAH who were taking a single oral PAH therapy. FREEDOM-EV demonstrated a significantly reduced risk for clinical worsening with oral treprostinil taken three times daily and did not uncover new safety signals in PAH patients. Sixty-one participants in the FREEDOM-EV trial volunteered for a hemodynamics sub-study. Pulmonary artery compliance (PAC), a ratio of stroke volume to pulmonary pulse pressure, significantly increased from Baseline to Week 24 in the oral treprostinil group compared with the placebo group (geometric mean 26.4% active vs. -6.0% placebo; ANCOVA p=0.007). There was a significant increase in cardiac output in the oral treprostinil group compared to the placebo group (geometric mean 11.3% active vs. -6.4% placebo; ANCOVA p=0.005) and a corresponding significant reduction in pulmonary vascular resistance (PVR) (geometric mean -21.5 active vs. -1.8% placebo; ANCOVA p=0.02) from Baseline to Week 24. These data suggest that increased compliance contributes to the physiological mechanism by which oral treprostinil improves exercise capacity and delays clinical worsening for patients with PAH.
| S-EPMC10024312 | biostudies-literature
Project description:The INSPIRE trial was a Phase 3, open-label, multicenter trial (LTI-301) that enrolled patients with pulmonary arterial hypertension (PAH) ≥ 18 years of age who transitioned to Yutrepia from nebulized treprostinil (Transition) or added Yutrepia to prostacyclin naïve patients on ≤2 nonprostacyclin oral therapies. The objectives of the trial were to evaluate the safety and tolerability of Yutrepia (dry-powder formulation of treprostinil) in patients with PAH. The primary safety measures were the incidence of adverse events (AEs) and serious AEs. Exploratory efficacy measures were also assessed during the trial. Transition patients initiated Yutrepia at a dose comparable to their nebulized treprostinil dose while prostacyclin naïve patients received 26.5-mcg QID; up-titration in 26.5-mcg increments was permitted for both groups. A total of 121 patients were enrolled, of which 29 patients discontinued from the trial, with the most common reason being AEs. Eighty percent of the Transition group and 96% of the prostacyclin naïve group titrated to a dose ≥79.5 mcg QID at Day 360, respectively, with one patient achieving a dose of 212-mcg QID. The most common AEs were cough, headache, upper respiratory tract infection, dyspnea, dizziness, throat irritation, diarrhea, chest discomfort, fatigue, and nasopharyngitis. Most of these events were considered treatment-related though mild to moderate in severity and expected for prostacyclin therapy administered by inhalation. In an evaluation of exploratory efficacy measures, patients remained stable or improved over the 1 year of treatment. Yutrepia was found to be a convenient, safe, and well-tolerated inhaled prostacyclin treatment option for PAH patients.
| S-EPMC9400582 | biostudies-literature
Project description:Treprostinil is a chemically stable analog of prostacyclin, and inhaled treprostinil was developed to deliver the effects directly to the pulmonary vasculature while minimizing systemic side effects. The objective of the study was to evaluate the efficacy on hemodynamics and exercise capacity, safety, and pharmacokinetics (PK) of inhaled treprostinil in Japanese patients with pulmonary arterial hypertension (PAH). Inhaled treprostinil was administered at three breaths (18 μg)/session four times daily, and the dose was gradually increased to a maximum of nine breaths (54 μg)/session. Endpoints included change in pulmonary vascular resistance index (PVRI) as primary, other efficacy parameters, safety, and PK. Seventeen PAH patients, the majority of whom (76.5%) had been receiving both an endothelin receptor antagonist (ERA) and a phosphodiesterase type-5 (PDE5) inhibitor/soluble guanylate cyclase (sGC) stimulator, received inhaled treprostinil. At Week 12, PVRI statistically decreased by -39.4 ± 25.5% (95% confidence interval: -52.6 to -26.3). The most frequently reported adverse events related to treprostinil were headache, cough, throat irritation, and hot flush. Regarding PK, there were no notable differences in the geometric mean C max and AUClast between Japanese and non-Japanese patients. Treatment with inhaled treprostinil using the dosing regimen approved in the United States resulted in significant improvement in hemodynamics, exercise capacity, and symptoms with a favorable tolerability and safety profile in Japanese patients. Inhaled treprostinil could be a valuable therapeutic option for Japanese patients with PAH, including those receiving a combination therapy with an ERA and a PDE5 inhibitor/sGC stimulator. Trial registration: JAPIC Clinical Trials Information [JapicCTI-194651].
| S-EPMC9906001 | biostudies-literature
Project description:Background and Objectives: Parenteral prostacyclins are crucial in the pharmacological treatment of pulmonary arterial hypertension (PAH). Indeed, subcutaneous administration of treprostinil has been associated with considerable clinical and hemodynamic improvement, right-sided heart reverse remodeling, and long-term survival benefit. However, evidence on patient perceptions about handling a subcutaneous infusion pump for self-treatment administration and nurse views about training the patients are lacking. This study aimed to describe the perception of PAH patients and nurses regarding the use of the new portable I-Jet infusion pump for the self-administration of subcutaneous treprostinil, as well as its real-world training needs. Materials and Methods: The study is an open, observational, prospective, single-center, non-interventional study. Patients with PAH on stable therapy with subcutaneous treprostinil were invited to take part in the study at their start of use of the portable I-Jet infusion pump for the self-administration of treatment. Participants filled in a questionnaire to report their satisfaction with the use of the pump, as well as their compliance, confidence, convenience, preferences, technical issues, and perceptions of the training they received. Results: Thirteen patients completed the questionnaire after being on the pump for 2 months: 69% were females and the mean age was 51 years. The most frequent PAH etiologies were congenital heart disease (46.2%) and idiopathic PAH (38.4%). Most patients were either World Health Organization (WHO) functional class II (53.8%) or III (46.2%). Ten patients (76.9%) found the pump easy and convenient to live with. All patients declared themselves to be fully compliant and confident in using the pump (n = 13) at the end of the study follow-up. Ten patients (76.9%) would choose the new pump in the future. None of the patients made reference to technical issues that required additional hospital visits. Eight patients (61.6%) reported that learning how to use the I-Jet infusion pump was easy or very easy, and none considered that further training was needed. One trainer nurse was interviewed and confirmed the satisfaction of patients and the simplicity of usage and training. Conclusions: PAH patients were highly satisfied with the use of the new portable I-Jet infusion pump for self-administering subcutaneous treprostinil. Convenience and ease of use were valuable and commonly reported features. Moreover, the training requirement was simple. These preliminary findings support the routine use of the I-Jet infusion pump.
| S-EPMC10058864 | biostudies-literature
Project description: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.
| S-EPMC6628532 | biostudies-literature
Project description:BackgroundApplication of Treprostinil (TRE) in the patients with single ventricle (SV) physiology is very limited, and the optimal dose for children has not been determined. In this study, we aimed to analyze plasma samples to assess the attainment of clinically therapeutic concentrations of TRE and its efficacy and safety in the treatment of pediatric functional SV pulmonary arterial hypertension (FSV-PAH)..MethodsPediatric patients with FSV-PAH were recruited in this study. IV TRE at an initial rate of 5 ng/kg/min was administered through the femoral vein with an increase in rate to 10 ng/kg/min every 30 minuntil the aiming dose of 80 ng/kg/min had been reached. The drug was gradually discontinued after 12 h of treatment at a stable dose. The mean postoperative pulmonary artery pressure (mPAP), pulmonary-to-systemic arterial pressure ratio (Pp/Ps), and the ratio between arterial oxygen partial pressure and inhaled oxygen concentration (PaO2/FiO2) were used to evaluate the efficacy of TRE treatment. A multiple linear regression model was used to explore the relevant factors associated with TRE blood concentration.ResultsA total of eight patients were enrolled in the investigation, with an age range of 2.5-9.9 years. The median stable dose of TRE was 70 ng/kg/min with a range of 55-75 ng/kg/min. The median subliminal dose was 55 ng/kg/min with a range of 25-75 ng/kg/min. A linear relationship was established between the TRE dose and the plasma concentration. TRE blood concentrations were associated with dose and patient height. After TRE treatment, mPAP, Pp/Ps, and PaO2/FiO2 were significantly improved (P<0.05).ConclusionsA linear relationship was found between the blood concentration of TRE and its dose. IV TRE was an effective therapy without serious side effects in pediatric patients with FSV-PAH.Trial registrationClinicalTrials.gov Identifier: NCT02865733.
| S-EPMC8350654 | biostudies-literature
Project description:Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).
| S-EPMC7068822 | biostudies-literature
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.
| S-EPMC8111525 | biostudies-literature
Project description:Treprostinil diolamine is the first oral prostacyclin approved for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity. Clinical studies have demonstrated modest benefit as monotherapy, whereas no difference in exercise capacity was observed with combination therapy. However, these trials were limited by subtherapeutic dosing owing to intolerable adverse effects. Prostacyclin-related adverse effects, such as nausea, diarrhea, headache, flushing, and jaw pain, are prevalent. More recent pharmacokinetic and clinical studies illustrate the dose-response relationship and the importance of achieving clinically effective doses. Therefore, efforts to improve tolerability are paramount. Oral treprostinil is recommended to be administered three times daily in order to facilitate more rapid titration, higher doses achieved, and improved tolerability. Oral treprostinil has also been studied in carefully selected, stable patients that transitioned from parenteral or inhaled therapy with close monitoring for late deterioration. Ongoing clinical trials will determine the long-term effects of higher doses of oral treprostinil on clinical outcomes. This review describes the clinical evidence and practical experience with the use of oral treprostinil for PAH.
| S-EPMC5941659 | biostudies-other
Project description:ObjectivesTo explore the pharmacokinetics (PK) of oral and intravenous (iv) lefamulin after single and multiple doses, and the effect of food on bioavailability.MethodsLefamulin PK was examined in four studies. In Study 1, PK was assessed in patients with acute bacterial skin and skin structure infections who received repeated iv lefamulin q12h (150 mg). In Study 2, a four-period crossover study, healthy subjects received a single dose of oral lefamulin [immediate-release (IR) tablet, 1 × 600 mg] in a fasted and fed state, oral lefamulin (capsule, 3 × 200 mg) in a fasted state, and iv lefamulin in a fasted state. In Study 3, a three-period crossover study, healthy males received a single oral lefamulin dose (IR) in the following states: fasted, fasted followed by a high-calorie meal 1 h post-dose, and fed. Study 4 had two parts; in part A, healthy males received a single lefamulin dose (IR) in a fasted and fed state; in part B, subjects received repeated doses of lefamulin (IR, q12h) or placebo. Adverse events (AEs) were recorded in each study.ResultsSingle and repeated dosing of iv and oral lefamulin resulted in comparable exposure. Intravenous and oral lefamulin (given fasted or with a meal 1 h post-dose) resulted in bioequivalence. Bioequivalence was not established between oral lefamulin in the fed state and iv or oral administration in the fasted state. All AEs were mild or moderate in severity, no serious AEs were reported, and no participant discontinued because of an AE.ConclusionsThe PK of lefamulin supports successful switch from iv to oral therapy; lefamulin was generally well tolerated.
| S-EPMC6449572 | biostudies-literature