The pharmacokinetics and pharmacodynamics of the prostacyclin analog 15AU81 in the anesthetized beagle dog

McNulty, Michael; Sailstad, Jeffrey; Steffen, Robert P.

doi:10.1016/0952-3278(93)90105-6

Cited by 35 publications

(14 citation statements)

References 2 publications

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“…Treprostinil (Remodulin® Injection, United Therapeutics Corporation, Research Triangle Park, NC) is a long‐acting, stable tricyclic benzindene analog of prostacyclin with similar pharmacological actions and acute hemodynamic effects to those observed with epoprostenol 7–9 . Furthermore, treprostinil is chemically stable at room temperature with neutral pH and a longer half‐life upon chronic administration (3 h; see companion manuscript 10 ).…”

mentioning

confidence: 99%

Absolute Bioavailability and Pharmacokinetics of Treprostinil Sodium Administered by Acute Subcutaneous Infusion

Wade

Baker

Roscigno

et al. 2004

The Journal of Clinical Pharma

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The objective of this study was to evaluate the absolute bioavailability and acute pharmacokinetics of treprostinil sodium administered by continuous, short-term subcutaneous infusion in normal subjects. Fifteen healthy volunteers received treprostinil via an intravenous infusion at 15 ng/kg/min over 150 minutes, followed by a 5- to 7-day washout and a subcutaneous infusion at the same rate administered over 150 minutes. Serial plasma samples were collected predosing, during dosing, and postdosing, and plasma treprostinil concentration levels were measured by a validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 25 pg/mL. Acute administration of treprostinil administered by subcutaneous infusion at a rate of 15 ng/kg/min for 150 minutes achieved a mean Cmax of 1.47 ng/mL. Mean AUC infinity values for intravenous and subcutaneous dosing were 3.52 and 3.97 ng.h/mL, respectively, resulting in a mean apparent absolute bioavailability of 113% for subcutaneous administration. It was possible that the area under of the curve for the intravenous administration was underestimated because most of the terminal elimination phase could not be documented due to the LLOQ of the assay. The mean apparent elimination half-life of treprostinil following subcutaneous administration was 1.38 hours, compared to 0.87 hours following intravenous administration. It was concluded that treprostinil administered by subcutaneous administration is completely absorbed, with a slightly longer half-life compared to intravenously administered treprostinil.

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mentioning

confidence: 99%

Absolute Bioavailability and Pharmacokinetics of Treprostinil Sodium Administered by Acute Subcutaneous Infusion

Wade

Baker

Roscigno

et al. 2004

The Journal of Clinical Pharma

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“…Treprostinil is a prostacyclin analogue that possesses similar pharmacological actions to epoprostenol, including vasodilatation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation [10,11]. However, epoprostenol therapy is associated with problems due to its short half-life (3-6 min) [12], necessitating continuous i.v.…”

mentioning

confidence: 99%

Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil

Barst¹,

Galiè²,

Naeije³

et al. 2006

European Respiratory Journal

297

231

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Pulmonary arterial hypertension (PAH) is fatal if untreated. Intravenous epoprostenol improves exercise capacity and haemodynamics in PAH, and increases survival in idiopathic PAH (IPAH). To evaluate the effects of subcutaneous (SC) treprostinil, a longeracting prostacyclin analogue, followed by the addition of other PAH therapies if needed, 860 PAH patients treated with SC treprostinil for up to 4 yrs were followed.Survival is reported as Kaplan-Meier estimates. For 332 IPAH patients with baseline haemodynamics, observed survival is also compared with predicted survival using the National Institute of Health formula.Out of the 860 patients, 199 (23%) discontinued due to adverse events, 136 (16%) died, 117 (14%) discontinued due to deterioration, 29 (3%) withdrew consent and 11 (1%) underwent transplantation. In total, 97 patients (11%) switched from SC treprostinil to an alternative prostacyclin analogue; bosentan was added in 105 patients (12%) and sildenafil in 25 (3%).In conclusion, survival was 87-68% over 1-4 yrs for all 860 patients and 88-70% over 1-4 yrs with subcutaneous treprostinil monotherapy. For the idiopathic pulmonary arterial hypertension subset with baseline haemodynamics (n5332), survival was 91-72% over 1-4 yrs. In contrast, predicted survival was 69-38% over 1-4 yrs. The safety profile for long-term subcutaneous treprostinil was consistent with previous short-term trials with no unexpected adverse events.

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“…[13] Treprostinil is [15] in relation to previously reported survival data (dotted line) obtained with intravenous epoprostenol according to McLaughlin et al [16] The dashed line illustrates the historically expected survival rates as reported by D'Alonzo et al [2] (reproduced from Lang et al, [15] with permission).…”

Section: Subcutaneous Treprostinilmentioning

confidence: 95%

The Role of Treprostinil in the Management of Pulmonary Hypertension

Skoro-Sajer

Lang

2008

American Journal of Cardiovascular Drugs

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Pulmonary arterial hypertension (PAH) is a severely disabling disorder characterized by sustained elevations of pulmonary vascular resistance, ultimately leading to right-heart failure and death. Intravenous epoprostenol has been widely used in patients with PAH, leading to long-term clinical benefits and improved survival. Epoprostenol has to be delivered through a permanently implanted intravenous catheter, with the potential of life-threatening complications. Thus, treprostinil, a stable prostacyclin analog suitable for subcutaneous administration, has been developed. Treprostinil is chemically stable at room temperature, has a long half-life (2-4 hours), and has similar pharmacologic properties with comparable hemodynamic effects as epoprostenol.A large, double-blind, placebo-controlled, multicenter, 12-week study confirmed the efficacy of subcutaneous treprostinil, by improving exercise capacity, Borg Dypnea Score (BDS), New York Heart Association (NYHA) class, and clinical signs and symptoms in patients with PAH. Subsequently, multiple observational studies reported the long-term effects of subcutaneous treprostinil. The long-term survival of patients treated with subcutaneous treprostinil was similar to that reported with intravenous epoprostenol. Pain at the infusion site has been a major drawback of subcutaneous treprostinil, hampering dose titration and leading to an 8-10% discontinuation rate. In addition, studies have examined the efficacy of intravenous treprostinil in the treatment of patients with PAH. An open-label study demonstrated that intravenous treprostinil improved exercise capacity, BDS, NYHA functional class, and hemodynamics at week 12 compared with baseline. Transitioning from intravenous epoprostenol to intravenous treprostinil is safe and effective. The dose of intravenous treprostinil has to be adjusted to approximately twice the dose of intravenous epoprostenol. Most patients have reported less severe adverse effects with intravenous treprostinil compared with intravenous epoprostenol. The assessment of the long-term efficacy and safety of continuous intravenous treprostinil requires further studies.

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The pharmacokinetics and pharmacodynamics of the prostacyclin analog 15AU81 in the anesthetized beagle dog

Cited by 35 publications

References 2 publications

Absolute Bioavailability and Pharmacokinetics of Treprostinil Sodium Administered by Acute Subcutaneous Infusion

Absolute Bioavailability and Pharmacokinetics of Treprostinil Sodium Administered by Acute Subcutaneous Infusion

Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil

The Role of Treprostinil in the Management of Pulmonary Hypertension

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