Pharmacokinetics and safety of single intravenous infusions of the adenosine agonist, AMP 579, in patients with end-stage renal insufficiency

The pharmacokinetics of an adenosine agonist (AMP 579) were characterized i n patients with end-stage renal disease compared to sex- and age-matched he althy volunteers. All study participants were administered single AMP 579 d oses of 50 mu g/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 pr otein binding. The safety of AMP 579 administration in renally impaired pat ients also was evaluated. AMP 579 was rapidly cleared from the systemic cir culation in all subjects as plasma concentrations were below the limit of d etection by 2 to 4 hours after terminating the infusion. Noncompartmental a nalysis yielded mean Values for the plasma AMP 579 concentration at the end of the 6-hour infusion (C-6h) Of 9.6 and 10.5 ng/mL and for systemic clear ances (CI) of 0.91 and 0.72 L/h/kg in renally impaired patients and healthy volunteers, respectively. Mean volumes of distribution (V-ss) in the renal ly impaired and healthy volunteers were 0.92 and 0.84 L/kg, and terminal el imination half-life values (t(1/2)) 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 r enally impaired and healthy volunteers, respectively. It was concluded that the pharmacokinetic parameters of AMP 579 were similar in both groups. The B-hour AMP 579 infusion was generally well tolerated by both renal patient s and healthy volunteers. There were no serious adverse events, and there w ere only two mild adverse events in I renally-impaired patient judged possi bly related to the study drug that quickly resolved. Th ere were no clinica lly significant changes in laboratory values or clinical evaluations during the study. There was a slight increase in heart rate during the infusion o f similar magnitude for both the renal patients and healthy volunteers. The se data suggest that AMP 579 may be administered to renally impaired patien ts with minimal cardiovascular effects and adverse events. These results in end-stage renal patients (worst-case scenario) indicate that dose adjustme nt in patients with renal insufficiency of any degree is not indicated in f uture studies of AMP 579.