Interspecies comparison of acivicin pharmacokinetics

Abstract

Pharmacokinetic studies with the amino acid antineoplastic agent, acivicin, were carried out in the Sprague-Dawley rat, cynomolgus monkey, and beagle dog. Data were analyzed together with previously published studies in the mouse and rhesus monkey. Log-log plots of body weight (B, kg) versus total body clearance (ClB, ml/min), elimination half-life (t1/2, hr), and volume of distribution (V, ml) in the five species were linear with high correlation coefficients (r greater than or equal to 0.98) despite large differences in the extent of nonrenal clearance in the various species (ranging from approximately 30% of the dose in the mouse to 90% in the dog). Linear regression on the plots yielded allometric expressions (ClB = 4.0 x B0.62; t1/2 = 1.8 x B0.31; V = 620 x B0.95) which were extrapolated mathematically to predict acivicin pharmacokinetic parameters in humans prior to the first clinical trials. Predicted versus measured (mean +/- SD, N = 21 patients) pharmacokinetic values in humans were: ClB (ml/min), 50 vs. 49 +/- 13; t1/2 (hr), 6.4 vs. 9.5 +/- 3.5; VB (ml/kg), 500 vs. 580 +/- 110. Thus, the animal data were successfully extrapolated to yield reasonable predictions of human pharmacokinetic parameters, despite varying extents of renal and nonrenal clearance in the species examined. With one exception, plasma concentration-time data in six species spanning a 3000-fold body weight range and a 120-fold dose range were plotted on a single curve after plasma concentrations were normalized for the dose administered and chronological times were adjusted for body weight to yield "physiological times."(ABSTRACT TRUNCATED AT 250 WORDS)