No evidence of desensitization to repeat dosing with treprostinil palmitil inhalation suspension (TPIS) for 32-consecutive days in hypoxia-challenged telemetered rats

Introduction: Continuous infusion with intravenous (IV) treprostinil (TRE) results in desensitization of the prostacyclin receptor and requires dose escalation to maintain its efficacy over time. It is unknown if desensitization to TPIS, a long-acting prodrug of TRE, occurs after repeat administration. Aim: Determine if desensitization occurs with TPIS after daily inhalation for 32-consecutive days. Methods: Male Sprague Dawley rats with a telemetry probe inserted in the right ventricle were exposed to acute inhaled hypoxia (Hx). The Hx-induced increase in right ventricular pulse pressure (∆RVPP) was measured before and every 4th day after daily TPIS (total daily delivered dose of 40 µg/kg) for 32-consecutive days. A comparison was made to continuous IV TRE (250 ng/kg/min) for 16-consecutive days. Blood samples were collected at each Hx challenge to measure the plasma TRE concentration. Results: There was no diminution in the ∆RVPP response to Hx after exposure to TPIS which averaged 15.49 mmHg before TPIS, and 5.01 mmHg on Day 0, 6.83 mmHg on day 16 and 7.01 mmHg on day 32. In contrast, the ∆RVPP response to Hx with IV TRE averaged 15.02 mmHg before IV TRE, and 7.77 mmHg on day 0 and 13.97 mmHg on day 16 indicating a diminution of effect by day 16 for IV TRE. The plasma TRE concentrations after TPIS ranged from 0.02 to 0.21 ng/ml but were higher with IV infused TRE and ranged from 2.54 to 13.35 ng/ml. Conclusions: Unlike IV infused TRE, there was no evidence for desensitization with TPIS for inhibition of Hx-induced pulmonary vasoconstriction in rats after daily adminstration via inhalation for 32-consecutive days.