| Reference | [1]. Curr Opin Investig Drugs. 2002 Apr;3(4):582-6.<br />
Treprostinil sodium Pharmacia.<br />
Chattaraj SC(1).<br />
Author information: (1)Mylan Pharmaceuticals Inc, Morgantown, WV 26504-4310, USA. [email protected]<br />
United Therapeutics Corp (UTC) is developing treprostinil sodium (Remodulin, UT-15), a stable structural analog of prostacyclin, for the potential treatment of primary pulmonary (arterial) hypertension (PAH), peripheral vascular disease (PVD) and other cardiovascular conditions [327593], including critical limb ischemia (CLI) [412483]. In August 2000, UTC submitted the initial, non-clinical sections of an NDA for the treatment of pulmonary hypertension [378906]. Treprostinil, which had previously been designated as an Orphan Drug, was also awarded Priority Review status by the US FDA in October 2000 [385864], [386271]. In December 2000, UTC agreed with the FDA that the NDA for treprostinil did not need to be presented to the Cardiovascular and Renal Drugs Advisory Committee, which was expected to allow UTC and the FDA to work towards the 6-month Priority Review timeline [393888]. On August 9, 2001, the advisory committee recommended approval of treprostinil and UTC refiled the NDA on the same day [418682]. In February 2002, the FDA issued an approvable letter for treprostinil injection for the treatment of PAH. The FDA proposed drug labeling for PAH consistent with the treatment of both primary and secondary pulmonary hypertension in patients with New York Heart Association (NYHA) Class II-IV symptoms. The approvable letter also stated that the FDA intended to approve treprostinil with a requirement that UTC subsequently conduct a post-marketing controlled clinical trial to verify and further describe the drug's clinical benefit [439278]. In February 2001, UTC submitted a marketing authorization application (MAA) in France for approval of treprostinil for the treatment of PAH. Upon approval of the MAA, UTC planned to file for Mutual Recognition in other European countries and was also preparing similar submissions to non-European countries [391986], [397958]. By early 2001, phase II trials of treprostinil for the treatment of CLI were underway [412483]. In March 2001, the company was planning a phase III pivotal study in late-stage PVD by the end of 2001 [424180]. In April 2000, UTC was issued US-06054486 for the method of treating PVD with treprostinil [364130]. In February 2000, UTC entered into an agreement with Paladin Labs for the exclusive Canadian distribution of treprostinil for the remainder of clinical trials and after regulatory approvals [357302]. In November 2000, UTC and Antigen Pharmaceuticals entered into a strategic alliance for the distribution of treprostinil in the UK and Ireland [390157]. In November 2000, Deutsche Banc Alex Brown predicted a sales potential of US $250 million to US $350 million [418736]. In August 2001, Merril Lynch predicted sales of US $10 million to $20 million in 2002 [420652].<br />
PMID: 12090728 [Indexed for MEDLINE]<br />
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[2]. N Engl J Med. 2021 Jan 28;384(4):325-334. doi: 10.1056/NEJMoa2008470. Epub 2021 Jan 13.<br />
Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease.<br />
Waxman A(1), Restrepo-Jaramillo R(1), Thenappan T(1), Ravichandran A(1), Engel P(1), Bajwa A(1), Allen R(1), Feldman J(1), Argula R(1), Smith P(1), Rollins K(1), Deng C(1), Peterson L(1), Bell H(1), Tapson V(1), Nathan SD(1).<br />
Author information: (1)From Brigham and Women's Hospital, Boston (A.W.); the University of South Florida, Tampa (R.R.-J.), and St. Vincent's Lung, Sleep, and Critical Care Specialists, Jacksonville (A.B.) – both in FL; the University of Minnesota, Minneapolis (T.T.); St. Vincent Medical Group, Indianapolis (A.R.); the Carl and Edyth Lindner Research Center at the Christ Hospital, Cincinnati (P.E.); University of California Davis Medical Center, Sacramento (R. Allen), and Cedars-Sinai, Los Angeles (V.T.); Arizona Pulmonary Specialists, Phoenix (J.F.); the Medical University of South Carolina, Charleston (R. Argula); United Therapeutics Corporation, Silver Spring, MD (P.S., K.R., C.D., L.P., H.B.); and Inova Fairfax Hospital, Falls Church, VA (S.D.N.).<br />
Comment in N Engl J Med. 2021 Jan 28;384(4):376-377. N Engl J Med. 2021 May 13;384(19):1869. N Engl J Med. 2021 May 13;384(19):1869-1870. N Engl J Med. 2021 May 13;384(19):1870. N Engl J Med. 2021 May 13;384(19):1870-1871. N Engl J Med. 2021 May 13;384(19):1871.<br />
BACKGROUND: No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear. METHODS: We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 μg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening. RESULTS: A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea. CONCLUSIONS: In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE ClinicalTrials.gov number, NCT02630316.).<br />
DOI: 10.1056/NEJMoa2008470 PMID: 33440084 [Indexed for MEDLINE]<br />
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[3]. Am J Health Syst Pharm. 2020 Apr 1;77(8):649-657. doi: 10.1093/ajhp/zxaa025.<br />
Compatibility of treprostinil sodium and dopamine hydrochloride during simulated Y-site administration.<br />
Bustin A(1), Ramsey EZ(1), Hanna BD(2), Kaushal G(3).<br />
Author information: (1)Department of Pharmacy Services, Children's Hospital of Philadelphia, Philadelphia, PA. (2)Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA. (3)Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA.<br />
PURPOSE: To evaluate the physical and chemical compatibilities of treprostinil sodium and dopamine hydrochloride. METHODS: Treprostinil sodium (4,000, 76,000, and 500,000 ng/mL) were mixed with dopamine hydrochloride (0.6, 3.2, 6, and 40 mg/mL). Samples were obtained at hours 0, 1, 2, and 4 for physical compatibility and chemical stability testing. Physical compatibility was assessed by visual examination and measurements of turbidity and pH. Drug concentrations were assessed using stability-indicating liquid chromatography mass spectrophotometry (LCMS) for treprostinil sodium and stability-indicating high-performance liquid chromatography (HPLC) for dopamine hydrochloride. RESULTS: Treprostinil sodium 4,000 and 76,000 ng/mL, when mixed with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL, were stable for 4 hours. Treprostinil sodium 500,000 ng/mL was stable when mixed with dopamine hydrochloride 0.6 mg/mL for 4 hours, but when mixed with dopamine hydrochloride 3.2, 6, and 40 mg/mL, significant precipitation was seen. CONCLUSION: Treprostinil sodium 4,000 and 76,000 ng/mL were stable for 4 hours during simulated Y-site coadministration with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL. Treprostinil sodium 500,000 ng/mL is stable when mixed with dopamine hydrochloride 0.6 mg/mL.<br />
DOI: 10.1093/ajhp/zxaa025 PMID: 32236454 [Indexed for MEDLINE]<br />
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[4]. Expert Opin Pharmacother. 2011 Nov;12(16):2583-93. doi: 10.1517/14656566.2011.622269.<br />
Inhaled treprostinil sodium for the treatment of pulmonary arterial hypertension.<br />
Ferrantino M(1), White RJ.<br />
Author information: (1)University of Rochester Medical Center, 400 Red Creek Dr, Suite 110, Rochester, NY 14623, USA.<br />
INTRODUCTION: Inhaled treprostinil sodium, a prostacyclin analog, is the most recent agent to receive FDA approval for the treatment of a fatal orphan disease: pulmonary arterial hypertension (PAH). AREAS COVERED: This article first reviews the data supporting the use of infusion prostacyclin and treprostinil as treatments for PAH. The authors then review inhaled treprostinil sodium: the compound and its properties, initial clinical evidence supporting its use and the pivotal data that support a role for inhaled treprostinil sodium in the treatment of patients with PAH. A broad PubMed literature search was done to identify the most current data on the use of treprostinil for PAH. Inhaled treprostinil received FDA approval to improve exercise tolerance in 2009, following the publication of several studies demonstrating its safety and its beneficial effect on hemodynamics, exercise capacity and quality-of-life measures. EXPERT OPINION: Inhaled treprostinil seems to have a similar efficacy profile as inhaled iloprost, although the demonstrated trough effect on exercise tolerance with treprostinil is an advantage. Perhaps more importantly, the longer half-life makes treprostinil more convenient with four-times-daily dosing. As compared with iloprost, inhaled treprostinil has practical advantages for patients (less frequent dosing, shorter inhalation times, once-daily preparation of the drug delivery device, and easier routine maintenance of the nebulizer), but direct comparisons about efficacy or durability of the treatment effect cannot be made in the absence of carefully controlled trials.<br />
DOI: 10.1517/14656566.2011.622269 PMID: 21988216 [Indexed for MEDLINE]<br />
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[5]. Am J Respir Crit Care Med. 2020 Mar 15;201(6):707-717. doi: 10.1164/rccm.201908-1640OC.<br />
Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial.<br />
White RJ(1), Jerjes-Sanchez C(2), Bohns Meyer GM(3), Pulido T(4), Sepulveda P(5), Wang KY(6), Grünig E(7), Hiremath S(8), Yu Z(9), Gangcheng Z(10), Yip WLJ(11), Zhang S(12), Khan A(13), Deng CQ(14), Grover R(14), Tapson VF(15); FREEDOM-EV Investigators.<br />
Collaborators: Svetliza GN, Lescano AJ, Bortman GR, Diez FA, Botta CE, Fitzgerald J, Feenstra E, Kermeen FD, Keogh AM, Williams TJ, Yousseff PP, Ng BJ, Smallwood DM, Dwyer NB, Brown MR, Lang IM, Steringer-Mascherbauer R, Arakaki JSO, Campos FTAF, de Amorim Correa R, de Souza R, Bohns Meyer GM, Moreira MAC, Yoo HHB, Lapa MS, Swiston J, Hirani N, Mehta S, Michelakis E, Sepulveda PA, Blancaire MMZ, Liu J, Shuyang Z, Pan L, Chunde B, Qun Y, Xiaoshu C, Zaixin Y, Li X, Hua Y, Gangcheng Z, Zhu X, Chen Y, Zhaozhong C, Yang Y, Daxin Z, Jieyan S, Nielsen-Kudsk JE, Carlsen J, Bourdin A, Hachulla E, Dromer C, Chaouat A, Reynaud-Gauber M, Seronde MF, Klose H, Halank M, Hoffken G, Ewert R, Rosenkranz S, Grunig E, Kruger U, Kronsbein J, Hauptmeier BM, Koch A, Held M, Lange TJ, Neurohr C, Wilkens H, Wilhelm Wirtz HR, Konstantinides S, Argyropoulou-Pataka P, Orfanos S, Hiremath S, Kerkar PG, Suresh PV, Baxi HA, Oomman A, Abhaichand RK, Arjun PKE, Chopra V, Mehrotra R, Rajput RK, Sawhney JPS, Bimalendu S, Sharma KH, Sastry BKS, Kramer MR, Segel MJ, Ben-Dov I, Berkman N, Yigla M, Adir Y, D'Alto M, Vizza CD, Scelsi L, Vitulo P, Pulido TR, Jerjes-Sanchez C, Boonstra A, Vonk MC, Sobkowicz B, Mularek-Kubzdela T, Torbicki A, Podolec P, Teik LS, Yip WLJ, Chang HJ, Kim HK, Park JB, Chang SA, Kim DK, Chang SA, Chung WJ, Song JM, Nissell M, Hjalmarsson C, Rundqvist B, Huang WC, Cheng CC, Hsu CH, Hsu HH, Wang KY, Coghlan JG, Kiely DG, Pepke-Zaba JW, Lordan JL, Corris PA, Cadaret L, Hansdottir S, Oudiz RJ, Badesch DB, Mathier M, Schilz R, Hill N, Waxman A, Markin CJ, Zwicke DL, Fisher M, Franco V, Sood N, Park MH, Allen R, Feldman JP, Balasubramanian V, Seeram VK, Bajwa A, Thompson AB 3rd, Migliore C, Elwing J, McConnell JW, Mehta JP, Rahaghi FF, Rame JE, Khan A, Patel B, Oren RM, Klinger JR, Alnuaimat H, Allen S, Harvey W, Eggert MS, Hage A, Miller CE, Awdish RLA, Cajigas H, Grinnan D, Trichon BH, McDonough C, White RJ, Rischard F.<br />
Author information: (1)Division of Pulmonary and Critical Care Medicine and the Mary M. Parkes Center, University of Rochester Medical Center, Rochester, New York. (2)Unidad de Investigación Clínica en Medicina, Monterrey, Mexico. (3)Complexo Hospitalar Santa Casa de Porto Alegre, Porto Alegre, Brazil. (4)Departamento de Cardioneumología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico. (5)Pontifica Universidad Católica de Chile, Santiago, Chile. (6)Taichung Veterans General Hospital, Taichung, Taiwan. (7)Thoraxclinic at University Hospital Heidelberg, Heidelberg, Germany. (8)Ruby Hall Clinic, Grant Medical Foundation, Pune, India. (9)Department of Cardiology, Xiangya Hospital of Central South University, Changsha, China. (10)Wuhan Asia Heart Hospital, Wuhan Shi, China. (11)Department of Cardiology, National University Heart Centre, Singapore, Singapore. (12)Peking Union Medical College Hospital, Beijing, China. (13)Oregon Health and Science University, Portland, Oregon. (14)United Therapeutics, Research Triangle Park, North Carolina; and. (15)Division of Pulmonary and Critical Care Medicine, Cedars Sinai Medical Center, Los Angeles, California.<br />
Comment in Am J Respir Crit Care Med. 2020 Mar 15;201(6):647-649.<br />
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).<br />
DOI: 10.1164/rccm.201908-1640OC PMCID: PMC7068822 PMID: 31765604 [Indexed for MEDLINE]
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