Comparative pharmacokinetics and pharmacodynamics of urocortins 1, 2 and 3 in healthy sheep

Abstract

BACKGROUND AND PURPOSE The urocortin (Ucn) peptides are emerging as potential therapeutic targets for heart disease. However, pharmacokinetic (PK) and pharmacodynamic (PD) data are lacking. Therefore, we investigated the PK/PD for all three Ucns. EXPERIMENTAL APPROACH Seven sheep received 1 µg·kg(-1) boluses of Ucn1, Ucn2 and Ucn3. Population PK/PD models were developed to describe the time course of the haemodynamic effects. RESULTS The population estimate for Ucn1 clearance (0.486 L·h(-1)) was lower than that for Ucn2 (21.7 L·h(-1)) and Ucn3 (220 L·h(-1)), while steady-state volumes of distribution were similar for Ucn1 and Ucn2 (∼8 L) but substantially larger for Ucn3 (23.5 L). Ucn1 disposition was adequately described by a two-compartment model, with a one-compartment model required for Ucn2 and Ucn3. The half-life for Ucn1 was 2.9 h (α phase) and 8.3 h (β phase), and 15.7 and 4.4 min for Ucn2 and Ucn3 respectively. All Ucns produced significant increases in heart rate, cardiac output and left ventricular systolic and mean arterial pressures, and decreases in left atrial pressure and peripheral resistance. Delayed-effect pharmacodynamic models best described the time course of haemodynamic responses, with effects more rapid and less prolonged for Ucn2 and Ucn3 than Ucn1. Similar and physiologically plausible estimated baseline (E(0)) effects were exhibited by all Ucns, whereas EC(50) values were generally greater for Ucn1. CONCLUSIONS AND IMPLICATIONS Relative to Ucn1, both the PK and haemodynamic responses to Ucn2 and Ucn3 occurred more rapidly. Our data provide important comparative information, useful to the rational design of future clinical studies.

Figure 1

Time course of haemodynamic responses following a 1 µg·kg⁻¹ bolus of Ucn1,Ucn2 and Ucn3 to seven conscious sheep. Data represent mean ± SEM. (A) Heart rate cardiac output and left ventricular systolic pressure. (B) Left atrial pressure, mean arterial pressure and the calculated total peripheral resistance.

Figure 2

Visual predictive check for Ucn1-3 in plasma (left panels) and corresponding changes in heart rate following Ucn dosing (right panels). Predicted median, 10th and 90th percentiles closely match corresponding observed percentiles, indicating the suitability of each of the developed PK/PD models. Closed circles represent actual observed data. For clear demonstration of the rapid PK/PD profiles for Ucn2 and Ucn3, all time axes are presented on a log scale.

Figure 3

Predictive check for the change in calculated total peripheral resistance (TPR) following bolus administration of Ucn1 (left), Ucn2 (middle) and Ucn3 (right) to sheep. Calculated TPR values were determined from MAP and CO observations, and predicted median, 10th and 90th percentiles were obtained using a composite model for MAP and CO. For clear demonstration of the rapid PK/PD profiles for Ucn2 and Ucn3, all time axes are presented on a log scale.