[Clinical pharmacokinetic trial of intravenous injection of recombinant human lymphotoxin-alpha derivative].

Background & Objective: Animal experiment showed that recombinant human lymphotoxin-alpha derivate (rhLTalpha-Da) could inhibit tumor growth,activate immunity, sensitize tumors to chemotherapy, and has low toxicity in vivo. rhLTalpha-Da won't accumulate after multiple administrations. This study was to investigate pharmacokinetic profile of rhLTalpha-Da in tumor patients to provide reference for phase II clinical trail.

Methods: The dosage of rhLTalpha-Da was 10, 20, and 33 microg x m(-2) x d(-1) according to phase I clinical endurance trial. rhLTalpha-Da was mixed with 100 ml 5% glucose solution, and then infused over 30 min on each of 5 consecutive days. Blood samples and urine samples were collected before and after infusion at different time points. Enzyme-linked immunosorbent assay (ELISA) and fluorescent bead immunoassay (FBI) were used to detect the concentration of rhLTalpha-Da in blood and urine. The main pharmacokinetic parameters were calculated by 3p97 pharmacokinetic program.

Results: From Feb. 2003 to Dec. 2003, 19 patients were enrolled. The linear range, specificity, precision, accuracy, and stability of ELISA method were satisfied. The lower limit of quantification (LLOQ) was 39 pg/ml. The linear range, sensitivity, specificity, intra-assay precision, and accuracy of FBI method were satisfied, but coefficient of variation of inter-assay precision was over 20%. rhLTalpha-Da in pharmacokinetics conformed to be a one-compartment open model:it had been eliminated quickly from serum and could not be detected 2 h after the cessation of infusion. The half lives (t1/2) of 33 microg x m(-2) x d(-1) and 20 microg x m(-2) x d(-1) of rhLTalpha-Da were (0.24+/-0.09) h and (0.25+/-0.10) h; the abundant volumes of distribution (Vd) were (35.8+/-1.6) L/m(2) and (43.3+/-26.0) L/m(2); the clearance (CL) were (343.36+/-63.23) ng x m(-2) x h(-1) and (269.60+/-24.52)ng x m(-2) x h(-1); the areas under concentration-time curve (AUC) were (74.6+/-18.4) ng x h x L(-1) and (99.0+/-17.8) ng x h x L(-1), respectively.

Conclusions: The pharmacokinetics of rhLTalpha-Da after infusion is fitted to one compartment model and its elimination is linear. There is no rhLTalpha-Da accumulation after multiple administrations.