Pulmonary Vascular Disease |

A Pharmacokinetic and Tolerability Comparison in Subjects Transitioning From Twice Daily to Three Times Daily Dosing of Oral Treprostinil FREE TO VIEW

R. James White, PhD; Karen Frutiger; Alison Theuer; Christine Weaver; Kevin Crawford; Kevin Laliberte
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University of Rochester, Rochester, NY

Chest. 2014;146(4_MeetingAbstracts):865A. doi:10.1378/chest.1963063
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SESSION TITLE: Pulmonary Hypertension

SESSION TYPE: Original Investigation Slide

PRESENTED ON: Tuesday, October 28, 2014 at 02:45 PM - 04:15 PM

PURPOSE: Treprostinil diolamine (TRE) is an extended release prostacyclin tablet for the treatment of pulmonary arterial hypertension (PAH). It is approved by the FDA as a twice (BID) or three times daily (TID) product. Oral TRE pharmacokinetics (PK) have been well studied in patients with PAH when administered BID, but there is little PK data for PAH patients taking drug TID. Early data suggested that a TID schedule was associated with better tolerability, and we hypothesized that a lower PK peak:trough ratio would be associated with better tolerability.

METHODS: We examined a cohort of patients in an ongoing open-label trial. Subjects were evaluated for PK twice - 14 days prior to transition to TID and within 5 weeks after transition. PK samples were collected before and 0.5, 1, 2, 4, 5, 6, 8, 10, 12 hours post morning dose (taken with food) to calculate peak:trough ratio, Tmax and AUC0-12. Tolerability was assessed by adverse events and efficacy by 6 minute walk distance and Borg dyspnea score.

RESULTS: The study enrolled 13 patients at a single center. Baseline demographics included a median age of 63 years (43-74) and median 6MWD of 307 meters (177-525). The average TRE BID dose was 8 mg BID (2-17.5 mg BID). Following transition, the average TRE TID dose was 6.6 mg TID (1.25-14 mg TID). Median 6MWD after transition was 323 meters (223-541). Nine of twelve patients completing both walks improved after transitioning to TID, and the average change in walk among the twelve was 13 m. Preliminary PK data demonstrate an average peak:trough ratio of 10 (3-26) with BID dosing and 5.5 (2.5-10) with TID dosing. The median Tmax for both regimens occurred 5 hours after the morning dose. The average (+/-SD) AUC0-12 was 49 +/- 23 and 59 +/- 31 ng*hr/mL for BID and TID dosing, respectively. Patient and physician impression of change indicated an improvement in side effects in 12 of the 13 patients comparing BID to TID dosing.

CONCLUSIONS: TID dosing of oral TRE reduces the peak to trough ratio; subjects reported improved tolerability profile with TID dosing.

CLINICAL IMPLICATIONS: TID dosing should be considered for new patients administered oral TRE and for patients having side effects with BID dosing.

DISCLOSURE: R. James White: Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Grant monies (from industry related sources): United Therapeutics Karen Frutiger: Grant monies (from industry related sources): United Therapeutics Alison Theuer: Grant monies (from industry related sources): United Therapeutics Christine Weaver: Grant monies (from industry related sources): United Therapeutics Kevin Crawford: Employee: United Therapeutics Kevin Laliberte: Employee: United Therapeutics

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