01 March 2017 by Ravikumar Sitapara

Incremental efficacy of an inhaled PDGFR inhibitor in combination with tadalafil and ambrisentan for the treatment of pulmonary arterial hypertension

Many patients with pulmonary arterial hypertension (PAH) fail to respond to combination therapy with PDEV inhibitors and endothelin receptor antagonists. We tested the hypothesis that a novel inhaled PDGFR kinase inhibitor, PK10571, in combination with Ambrisentan and Tadalafil would provide incremental benefit in an animal model of severe PAH. AAV5/6.2CMV PDGF B was administered by pulmonary insufflation to male SD rats in order to overexpress PDGFBB in the lung. Four weeks later, SU5416 was given and rats housed in a hypoxia chamber at FiO2 10% for 3 weeks. After PAH had developed, PK10571 was administered either alone (0.25mg/kg twice daily via inhalation route) or in combination with Ambrisentan and Tadalafil (10mg/kg, oral gavage; once daily) for 28 days. AAV-PDGFB alone did not result in PAH. Overexpression of PDGF B resulted in a decrease in total PDGFRβ. However, subjecting these animals to SU5416/hypoxia dramatically increased pPDGFR β/PDGFR. Right ventricular systolic pressure (RVSP) was significantly decreased in rats treated with Ambrisentan+Tadalafil (TA-V) or PK10571 (V-PK) alone compared to vehicle (V-V). Combination treatment (TA-PK) provided additional benefit (V-V, 62.64±4.07; TA-V, 42.89±2.23; V-PK, 44.30±1.88; TA-PK, 33.24±1.15, mm Hg, p<0.01 TA-V, V-PK, or TA-PK vs V-V; p<0.01 TA-PK vs TA-V or V-PK). RV hypertrophy (RV/(LV+IVS)) was significantly decreased in rats treated with TA-V, V-PK or TA-PK compared to V-V, and TA-PK provided additional reduction in RVH (V-V, 0.505±0.03; TA-V, 0.376±0.02; V-PK, 0.36±0.01; TA-PK, 0.277±0.01, p<0.01 TA-V, V-PK, or TA-PK vs V-V; p<0.05 TA-PK vs TA-V or V-PK). The incremental efficacy of combination therapy (TA-PK) was associated with a decrease in pPDGFR β/PDGFRβ. These data show that Inhaled PK10571 was as effective as treatment with Tadalafil plus Ambrisentan in the AAV-PDGFB SU5416/Hypoxia rat model of PAH. Combination treatment of inhaled PK10571 plus Tadalafil and Ambrisentan provided additional benefit compared to Tadalafil plus Ambrisentan.

Key Contributors

Ravikumar Sitapara, Chuluun Sugarragchaa, Lawrence Zisman Pulmokine, Rensselaer, New York, USA


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