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Low Oral Bioavailability of RPL554, a First-in-Class Dual PDE3/4 Inhibitor, Demonstrates that Its Nebulized, Inhaled Formulation Is Appropriate for Delivering Optimal Pulmonary Dose
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A3022 - Low Oral Bioavailability of RPL554, a First-in-Class Dual PDE3/4 Inhibitor, Demonstrates that Its Nebulized, Inhaled Formulation Is Appropriate for Delivering Optimal Pulmonary Dose
Author Block: K. B. Newman1, M. Armstrong2, B. T. Maurer3, J. Ayrton1, R. Causon1; 1Verona Pharma, London, United Kingdom, 2Quintiles Phase 1 Services, Quintiles IMS, Overland Park, KS, United States, 3Verona Pharma, plc, White Plains, NY, United States.
Introduction: RPL554 is an inhaled dual PDE3/4 inhibitor that has been shown to possess bronchodilator, bronchoprotective, and anti-inflammatory effects, and is being studied as a treatment of respiratory diseases. Since a proportion of any nebulized, inhaled medication is deposited in the mouth and then swallowed by the subject, we sought to assess the potential contribution of absorption of RPL554 from the gastrointestinal (GI) tract to its systemic exposure. The objective of this study was to determine the proportion of the dose that enters the bloodstream via the GI tract.
Methods: This was a randomized, complete block, 2 way cross-over study to investigate the bioavailability and pharmacokinetics (PK) of RPL554 in healthy volunteers. A total of 12 male subjects (6 Caucasian, 6 African-American) were enrolled into the study with a mean age of 25.4 years. Each subject received a total of two 6 mg doses of RPL554 via nebulizer, one with and one without a charcoal block. Each of the single treatments was separated by 3 to 14 days. In accordance with the randomization schedule, an aqueous suspension of activated charcoal (Actidose Aqua®) was administered orally pre-dose, 12 minutes and 1, 2 and 4 hours post-dose. PK sampling was performed at 15 and 30 minutes and 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 40 and 48 hours post-dose. Plasma RPL554 was determined using a validated UPLC-MS/MS bioanalytical method.
Results: All 12 subjects completed the study. The mean area under the curve (AUC0-∞) was 16.0 ng*hr/mL (±3.75) after administration of RPL554 alone, and 14.1 ng*hr/mL (±2.07) for RPL554 plus activated charcoal. The mean half-life in blood was 11.9 hours (±2.02). As measured by the relative bioavailability fraction of RPL554, 10.4 percent of the inhaled dose entered the bloodstream via the GI tract. RPL554 was well tolerated without any nausea or vomiting.
Conclusions: In this study, the low oral bioavailability and plasma concentrations of RPL554 seen as a result of the swallowed medication suggests only a limited contribution to the systemic effects of RPL554 after nebulized administration. These results indicate that the nebulized, inhaled formulation of RPL554 is an appropriate form of administration to human subjects. Additionally, the plasma half-life is consistent with earlier data, supporting a twice daily dosing regimen in patients with respiratory disorders.
Author Block: K. B. Newman1, M. Armstrong2, B. T. Maurer3, J. Ayrton1, R. Causon1; 1Verona Pharma, London, United Kingdom, 2Quintiles Phase 1 Services, Quintiles IMS, Overland Park, KS, United States, 3Verona Pharma, plc, White Plains, NY, United States.
Introduction: RPL554 is an inhaled dual PDE3/4 inhibitor that has been shown to possess bronchodilator, bronchoprotective, and anti-inflammatory effects, and is being studied as a treatment of respiratory diseases. Since a proportion of any nebulized, inhaled medication is deposited in the mouth and then swallowed by the subject, we sought to assess the potential contribution of absorption of RPL554 from the gastrointestinal (GI) tract to its systemic exposure. The objective of this study was to determine the proportion of the dose that enters the bloodstream via the GI tract.
Methods: This was a randomized, complete block, 2 way cross-over study to investigate the bioavailability and pharmacokinetics (PK) of RPL554 in healthy volunteers. A total of 12 male subjects (6 Caucasian, 6 African-American) were enrolled into the study with a mean age of 25.4 years. Each subject received a total of two 6 mg doses of RPL554 via nebulizer, one with and one without a charcoal block. Each of the single treatments was separated by 3 to 14 days. In accordance with the randomization schedule, an aqueous suspension of activated charcoal (Actidose Aqua®) was administered orally pre-dose, 12 minutes and 1, 2 and 4 hours post-dose. PK sampling was performed at 15 and 30 minutes and 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 40 and 48 hours post-dose. Plasma RPL554 was determined using a validated UPLC-MS/MS bioanalytical method.
Results: All 12 subjects completed the study. The mean area under the curve (AUC0-∞) was 16.0 ng*hr/mL (±3.75) after administration of RPL554 alone, and 14.1 ng*hr/mL (±2.07) for RPL554 plus activated charcoal. The mean half-life in blood was 11.9 hours (±2.02). As measured by the relative bioavailability fraction of RPL554, 10.4 percent of the inhaled dose entered the bloodstream via the GI tract. RPL554 was well tolerated without any nausea or vomiting.
Conclusions: In this study, the low oral bioavailability and plasma concentrations of RPL554 seen as a result of the swallowed medication suggests only a limited contribution to the systemic effects of RPL554 after nebulized administration. These results indicate that the nebulized, inhaled formulation of RPL554 is an appropriate form of administration to human subjects. Additionally, the plasma half-life is consistent with earlier data, supporting a twice daily dosing regimen in patients with respiratory disorders.
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