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REPEATED ORAL ADMINISTRATION OF THE SELECTIVE PROSTACYCLIN RECEPTOR AGONIST SELEXIPAG DOES NOT CAUSE TACHYPHYLAXIS IN SPONTANEOUSLY HYPERTENSIVE RATS
A1558 JACC March 17, 2015 Volume 65, Issue 10S
Pulmonary Hypertension and Venous Thrombo-embolic Disease Repeated Oral Administration of the Selective Prostacyclin Receptor Agonist Selexipag Does Not Cause Tachyphylaxis in Spontaneously Hypertensive Rats Poster Contributions Poster Hall B1 Sunday, March 15, 2015, 3:45 p.m.-4:30 p.m. Session Title: Pulmonary Arterial Hypertension: Assessment and Therapy Abstract Category: 24. Pulmonary Hypertension and Pulmonary Thrombo-embolic Disease Presentation Number: 1214-172 Authors: Keith Morrison, Daniel Wanner, John Gatfield, Carmela Gnerre, Patrick Hess, Martine Clozel, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
Background: Selexipag, an orally available, selective prostacyclin (PGI2) receptor (IP receptor) agonist, significantly decreased pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH) in a phase 2 clinical trial. Selexipag is structurally different from PGI2. Reduced clinical efficacy of PGI2 analogs can be observed in patients with PAH following repeated or continuous administration via parenteral routes, in a process called tachyphylaxis. This study used a rat model to investigate tachyphylaxis in response to repeated oral administration of selexipag.
Methods: Spontaneously hypertensive rats (SHRs) were implanted with telemetry recording systems and mean arterial blood pressure (MAP) and heart rate (HR) were monitored. Selexipag was administered either by oral gavage (b.i.d.), or incorporated in normal rat chow (food admix). The effects of the PGI2 analog treprostinil, administered via continuous i.v. infusion, were measured in comparison. Results: A sub-maximal dose of selexipag (oral gavage, 10 mg/kg, b.i.d.) decreased MAP in SHRs (maximum decrease: 21 ± 6 mmHg) in a reproducible manner upon each administration of drug over the duration of the experiment (5 days). Selexipag (food admix, 10, 30, 100 and 300 mg/kg/day) caused a dose-dependent reduction in MAP. The effect of selexipag was maintained for 4 days at each dose level. Plasma concentrations of ACT-333679, the active metabolite of selexipag, were increased at each dose level. A submaximal dose of selexipag (food admix, 100 mg/kg/day) decreased MAP for up to 10 days. MAP returned to pre-drug levels on cessation of drug administration in both food admix experiments. Continuous infusion of an equi-effective dose of the PGI2 analog treprostinil (30 µg/kg/ hr, i.v.) caused a transient reduction in MAP, which returned to pre-drug levels within 36 hours, despite the continued presence of drug in plasma.
Conclusion: Repeated oral administration of selexipag does not induce tachyphylaxis in a rat model of systemic hypertension, whereas the response to continuous infusion of an equi-effective dose of a PGI2 analog is not maintained. Long-term use of selexipag may be associated with maintained efficacy.
Pulmonary Hypertension and Venous Thrombo-embolic Disease Repeated Oral Administration of the Selective Prostacyclin Receptor Agonist Selexipag Does Not Cause Tachyphylaxis in Spontaneously Hypertensive Rats Poster Contributions Poster Hall B1 Sunday, March 15, 2015, 3:45 p.m.-4:30 p.m. Session Title: Pulmonary Arterial Hypertension: Assessment and Therapy Abstract Category: 24. Pulmonary Hypertension and Pulmonary Thrombo-embolic Disease Presentation Number: 1214-172 Authors: Keith Morrison, Daniel Wanner, John Gatfield, Carmela Gnerre, Patrick Hess, Martine Clozel, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
Background: Selexipag, an orally available, selective prostacyclin (PGI2) receptor (IP receptor) agonist, significantly decreased pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH) in a phase 2 clinical trial. Selexipag is structurally different from PGI2. Reduced clinical efficacy of PGI2 analogs can be observed in patients with PAH following repeated or continuous administration via parenteral routes, in a process called tachyphylaxis. This study used a rat model to investigate tachyphylaxis in response to repeated oral administration of selexipag.
Methods: Spontaneously hypertensive rats (SHRs) were implanted with telemetry recording systems and mean arterial blood pressure (MAP) and heart rate (HR) were monitored. Selexipag was administered either by oral gavage (b.i.d.), or incorporated in normal rat chow (food admix). The effects of the PGI2 analog treprostinil, administered via continuous i.v. infusion, were measured in comparison. Results: A sub-maximal dose of selexipag (oral gavage, 10 mg/kg, b.i.d.) decreased MAP in SHRs (maximum decrease: 21 ± 6 mmHg) in a reproducible manner upon each administration of drug over the duration of the experiment (5 days). Selexipag (food admix, 10, 30, 100 and 300 mg/kg/day) caused a dose-dependent reduction in MAP. The effect of selexipag was maintained for 4 days at each dose level. Plasma concentrations of ACT-333679, the active metabolite of selexipag, were increased at each dose level. A submaximal dose of selexipag (food admix, 100 mg/kg/day) decreased MAP for up to 10 days. MAP returned to pre-drug levels on cessation of drug administration in both food admix experiments. Continuous infusion of an equi-effective dose of the PGI2 analog treprostinil (30 µg/kg/ hr, i.v.) caused a transient reduction in MAP, which returned to pre-drug levels within 36 hours, despite the continued presence of drug in plasma.
Conclusion: Repeated oral administration of selexipag does not induce tachyphylaxis in a rat model of systemic hypertension, whereas the response to continuous infusion of an equi-effective dose of a PGI2 analog is not maintained. Long-term use of selexipag may be associated with maintained efficacy.