title: Dose proportionality of treprostinil sodium administered by continuous subcutaneous and intravenous infusion.
abstract: This study assessed the relationship between dose and plasma concentration following administration of treprostinil sodium infusion therapy in pulmonary arterial hypertension patients. This was a multicenter, open-label, multiple-cohort, steady-state, pharmacokinetic study in subjects with pulmonary arterial hypertension receiving treprostinil by continuous intravenous or subcutaneous infusion at doses between 10 and 125 ng/kg/min. A blood sample was obtained from each patient at steady state and analyzed via a liquid chromatography/tandem mass spectrometry method. Forty-nine subjects receiving treprostinil were enrolled. Treprostinil doses ranged from 12.1 to 125 ng/kg/min; treprostinil plasma concentrations ranged from 14.9 to 18 248 pg/mL. Linear regression analysis revealed a correlation between treprostinil dose and treprostinil plasma concentration with an R2 value of 0.561. Using a power model to assess dose proportionality, the estimated nonproportionality parameter was 0.641 (95% confidence interval: 0.083-1.199), reflecting consistency with dose proportionality. Subset linear regression analysis, which excluded 2 subjects with anomalous treprostinil plasma concentrations, increased the R2 value to 0.796. Using a power model to assess dose proportionality of this subset, the estimated nonproportionality parameter was 0.941 (95% confidence interval: 0.809-1.073). This study supports previous findings of linearity at lower doses up to 15 ng/kg/min and demonstrates linearity at treprostinil doses up to 125 ng/kg/min.
authors: Clinical Affairs, United Therapeutics Corporation, One Park Drive, 4th Floor, Research Triangle Park, NC 27709, USA. csmcswain@unither.com
authors: C Shane
authors: CS
authors: McSwain
authors: Ray
authors: R
authors: Benza
authors: Shelley
authors: S
authors: Shapiro
authors: Nicholas
authors: N
authors: Hill
authors: Robert
authors: R
authors: Schilz
authors: C Gregory
authors: CG
authors: Elliott
authors: Dianne L
authors: DL
authors: Zwicke
authors: Ronald J
authors: RJ
authors: Oudiz
authors: James P
authors: JP
authors: Staszewski
authors: Carl P
authors: CP
authors: Arneson
authors: Michael
authors: M
authors: Wade
authors: David
authors: D
authors: Zaccardelli
authors: Vallerie
authors: V
authors: McLaughlin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use; D002853:Chromatography, Liquid; D004077:Digoxin / Q000008:administration & dosage / Q000627:therapeutic use; D004232:Diuretics / Q000008:administration & dosage / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010100:Oxygen / Q000008:administration & dosage / Q000627:therapeutic use; D058986:Phosphodiesterase 5 Inhibitors; D012044:Regression Analysis
chemical_list: D000925:Anticoagulants; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004232:Diuretics; D058986:Phosphodiesterase 5 Inhibitors; D004077:Digoxin; D011464:Epoprostenol; C427248:treprostinil; D010100:Oxygen