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The pharmacokinetics of an adenosine agonist (AMP 579) were characterized in patients with end-stage renal disease compared to sex- and age-matched healthy volunteers. All study participants were administered single AMP 579 doses of 50 micrograms/kg as a 6-hour, constant-rate intravenous infusion. Serial blood samples were obtained for measurement of plasma AMP 579 concentration, and predose samples were collected for determination of AMP 579 plasma protein binding. The safety of AMP 579 administration in renally impaired patients also was evaluated. AMP 579 was rapidly cleared from the systemic circulation in all subjects as plasma concentrations were below the limit of detection by 2 to 4 hours after terminating the infusion. Noncompartmental analysis yielded mean values for the plasma AMP 579 concentration at the end of the 6-hour infusion (C6 h) of 9.6 and 10.5 ng/mL and for systemic clearances (Cl) of 0.91 and 0.72 L/h/kg in renally impaired patients and healthy volunteers, respectively. Mean volumes of distribution (Vss) in the renally impaired and healthy volunteers were 0.92 and 0.84 L/kg, and terminal elimination half-life values (t1/2) were 1.61 and 1.33 hours, respectively. The extent to which AMP 579 is bound to plasma protein was not altered in renally impaired patients since the free fractions were 4.0% and 3.4% for renally impaired and healthy volunteers, respectively. It was concluded that the pharmacokinetic parameters of AMP 579 were similar in both groups. The 6-hour AMP 579 infusion was generally well tolerated by both renal patients and healthy volunteers. There were no serious adverse events, and there were only two mild adverse events in 1 renally impaired patient judged possibly related to the study drug that quickly resolved. There were no clinically significant changes in laboratory values or clinical evaluations during the study. There was a slight increase in heart rate during the infusion of similar magnitude for both the renal patients and healthy volunteers. These data suggest that AMP 579 may be administered to renally impaired patients with minimal cardiovascular effects and adverse events. These results in end-stage renal patients (worst-case scenario) indicate that dose adjustment in patients with renal insufficiency of any degree is not indicated in future studies of AMP 579.

The pharmacokinetics of an adenosine agonist, AMP 579, following intravenous administration were evaluated. Single AMP 579 doses of 20 to 150 micrograms/kg were infused intravenously over 6 hours using a constant-rate or two-step rate of infusion to healthy male volunteers. Plasma and urine samples were collected for measurement of AMP 579 concentration using a validated HPLC assay. An assessment of safety and tolerability was also performed. Based on a noncompartmental method of analysis, the pharmacokinetics of AMP 579 were characterized by rapid systemic clearance (0.77 to 0.85 L/h/kg), a moderate steady-state volume of distribution (0.80 to 0.94 L/kg), and a short terminal elimination half-life (0.84 to 1.13 h). AMP 579 exhibited dose (infusion rate)-proportional pharmacokinetics over the dose range. In addition, little or no unchanged AMP 579 was found in the urine. The primary cardiovascular pharmacodynamic response that was observed was a dose-related increase in mean ventricular heart rate. Fifteen minutes prior to the end of the infusion, volunteers administered the highest dose (150 micrograms/kg) exhibited a mean (range) 59% (36%-69%) increase in heart rate as compared to a mean (range) 18% (0%-73%) increase for the placebo group. No clinically relevant changes in the systolic or diastolic blood pressure were observed. The information obtained in this study should allow the design of AMP 579 dosage regimens that would maximize plasma AMP 579 concentrations and minimize the incidence of adverse events.