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Pharmacokinetics of 2′,3′‐Dideoxycytidine in Rats: Application to Interspecies Scale‐up

Abstract— The effects of dose on the pharmacokinetics of 2′,3′‐dideoxycytidine (DDC), a potent inhibitor of HIV replication, have been studied in rats. DDC was administered intravenously at doses of 10, 50, 100 and 200 mg kg−1. Plasma and urine drug concentrations were determined by HPLC. Non‐compartmental pharmacokinetic parameters were calculated by area/moment analysis. DDC plasma concentrations declined rapidly with a terminal half‐life of 0·98 ± 0·18 h (mean± s.d.). No statistically significant differences were observed in pharmacokinetic parameters between the four doses. Total, renal and nonrenal clearance values were independent of dose and averaged 1·67 ± 0·24, 0·78 ± 0·11, and 0·89 ± 0·27 L h−1 kg−1, respectively. Approximately 50% of the dose was excreted unchanged in urine. Steady state volume of distribution was also independent of dose and averaged 1·2±0·21 L kg−1. Protein binding of DDC to rat serum proteins was independent of drug concentration with the fraction of drug bound averaging 0·45 ± 0·12. Thus, the disposition pattern of DDC in the rat is independent of the administered dose even at high doses. Significant interspecies correlations were found for total, renal and non‐renal clearance and steady state volume of distribution. Interspecies scaling resulted in superimposable plasma DDC concentration‐time profiles from four laboratory animal species and man. Thus, plasma DDC concentrations in humans can be predicted from pharmacokinetic parameters obtained in laboratory animals.