Single-Dose Pharmacokinetics of Leuprolide in Humans Following Intravenous and Subcutaneous Administration

Abstract

A group of six normal adult male volunteers was divided into two groups (I and II) who received bolus intravenous and subcutaneous 1-mg doses of leuprolide. The study was of a randomized, complete-crossover design. Blood was collected from 0 to 48h postdosing, and plasma was analyzed for leuprolide using a radioimmunoassay procedure. The data from the intravenous doses were fitted to a two-compartment open model with elimination from the central compartment, assuming a bolus (instantaneous) injection. The data from the subcutaneous doses were fitted to a two-compartment open model with elimination from the central compartment and first-order (monoexponential) absorption from the injection site. Statistical moments were also calculated for both sets of data. The mean beta half-life after the intravenous dosings was 2.9h and after the subcutaneous dosings was 3.6h. The difference between these two values, as well as those for plasma clearance, variance in residence time, and volume of distribution at steady state was not statistically significant; however, the differences between the mean values of k21, k12, kel, apparent volume of distribution of the central compartment, mean residence time, and area under the moment curve for the routes of administration were significant (p<0.05). The mean residence time following the intravenous dosings averaged 3.1h and following the subcutaneous dosings averaged 4.3 h, indicating an average mean residence time at the subcutaneous injection site of 1.2h. The mean volume of distribution at steady state from the intravenous and subcutaneous doses were 26.5 and 37.1L, respectively. Following the subcutaneous dosings, the mean calculated peak circulating level was 32.3ng/mL, which was reached 0.6h following administration. Based upon mean areas under zero to infinity plasma time-concentration curves, the bioavailability of subcutaneously administered leuprolide was estimated to be ˜94%.