u-62840 and Kidney-Failure--Chronic

Treprostinil diolamine sustained release (UT-15C SR) is being evaluated as an oral therapy for pulmonary arterial hypertension. This study evaluated the pharmacokinetics (PKs) of treprostinil following administration of UT-15C SR in subjects with end-stage renal disease (ESRD) compared with healthy subjects with normal renal function (NRF) and the effect of hemodialysis on the PK parameters of treprostinil. Eight ESRD subjects (requiring dialysis, mean creatinine clearance = 11.5 mL/min) received 2 single doses of 1 mg of UT-15C SR (separated by 2 weeks), with the first dose given immediately after dialysis and the second given 4 hours before the start of dialysis. Eight NRF subjects received a single dose of 1 mg of UT-15C SR. The median Cmax, AUC0-inf, and t1/2 of treprostinil were 680 pg/mL, 3240 hours pg/mL, and 2.35 hours, respectively, in ESRD subjects dosed after dialysis and were 551 pg/mL, 3152 hours pg/mL, and 2.05 hours, respectively, in ESRD subjects dosed before dialysis. In comparison, corresponding values were 730 pg/mL, 3726 hours pg/mL, and 3.54 hours, respectively, in NRF subjects. UT-15C SR of 1 mg was well tolerated by NRF and ESRD subjects. The most frequent adverse event was headache and nausea. There was no substantial difference in treprostinil PKs between ESRD and NRF subjects following administration of UT-15C SR tablets. Hemodialysis did not have clinically important effect on treprostinil PK in ESRD subjects.

Topics: Adult; Antihypertensive Agents; Area Under Curve; Case-Control Studies; Delayed-Action Preparations; Epoprostenol; Female; Half-Life; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Time Factors

Use of the vasodilator midodrine for the treatment of treprostinil-induced hypotension is reported.. Intradialytic hypotension is a common complication of dialysis that increases patient mortality due to suboptimal ultrafiltration and interruption of hemodialysis. Midodrine is an α1 vasoconstrictor commonly used for the treatment of pulmonary arterial hypertension (PAH) and intradialytic hypotension. The safety of midodrine dosing at greater than 30 mg daily has not been established to date. A 49-year-old African-American man with a history of PAH and end-stage renal disease (ESRD) was receiving hemodialysis (HD) 3 times weekly. Subcutaneous treprostinil infusions were initiated for PAH, subsequently causing hypotension, with predialysis blood pressure values as low as 60/50 mm Hg. During a 6-month follow-up period, 38 of 62 dialysis sessions were interrupted or discontinued due to severe intradialytic hypotension. Counteraction of treprostinil effects was achieved by increasing the total daily midodrine dose from 30 mg to 90 mg over 6 months, with no remarkable adverse effects. In previously reported cases, maximum midodrine daily doses of 30 mg in nondialysis patients and 25 mg in patients with ESRD receiving hemodialysis were reported. The patient described here received a total daily dose of 90 mg, including 60 mg administered in divided doses for daily maintenance and 30-mg intradialytic doses; this was the highest daily midodrine dose reported to date.. A 49-year-old patient tolerated 60-mg daily doses of midodrine along with 30-mg intradialytic doses for the management of treprostinil-induced hypotension and prevention of HD interruption, without adverse effects.

Topics: Antihypertensive Agents; Dose-Response Relationship, Drug; Epoprostenol; Humans; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Midodrine; Pulmonary Arterial Hypertension; Renal Dialysis