Pharmacokinetics and Pharmacodynamics of Ketanserin

Article Outline

• Take Home Message
• Introduction
• Materials and Methods
• Results
• Discussion, Clinical Relevance and Conclusion
• Copyright

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Take Home Message 

Ketanserin reduces agonist-induced platelet aggregation in some, but not all horses.

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Introduction 

The changes in digital hemodynamics during laminitis implicate 5-hydroxytryptamine (5-HT) produced by activated platelets. This study aimed to determine the pharmacokinetics and pharmacodynamics of ketanserin, a 5-HT receptor antagonist, in healthy adult horses.

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Materials and Methods 

Plasma concentrations of ketanserin were determined by HPLC with mass spectrometry after IV administration (100 mcg/kg). The plasma drug concentration-time profile was analyzed using noncompartmental and compartmental approaches. Pharmacodynamics were measured using ADP- and collagen-induced platelet aggregation, and a model was developed to describe the observed drug effects.

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Results 

A two-compartment linear pharmacokinetic model described ketanserin's plasma concentration-time profile; terminal half-life was 8.25 hour, volume of distribution was 11.6 L, AUC was 5.98 mg•min/liter and clearance was 0.01 L/min. Two populations of horses were identified, one in which ketanserin reduced agonist-induced platelet aggregation and one in which platelet responses were not altered. In responding horses, ADP-induced platelet aggregation 8 hours after treatment decreased from 71.2±5.3% to 45.7±9% and collagen-induced aggregation from 72.3±5.7% to 43.4±17.2% (p<0.001). After 24 hours, platelet aggregation had returned to baseline values. Ketanserin pharmacodynamics exhibits a hysteresis and modeling suggests its dynamics can be described using an indirect response model.

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Discussion, Clinical Relevance and Conclusion 

A pharmacokinetic model was developed to describe the plasma concentration-time profile of ketanserin in healthy horses, which suggests ketanserin's time-course of activity can be described by an indirect response model. Additional studies will be performed to determine whether alterations in platelet and laminar microvascular function are related or independent effects of the drug.