Non-clinical Pharmacokinetic And Pharmacodynamic Study Of Humanized Anti-CD20 Monoclonal Antibody

AIM: To study the non-clinical pharmacokinetics (PK) and pharmacodynamics (PD) of rh-anti-CD20zumAb in rhesus monkeys.METHODS: A flow cytometric method, which could satisfy the requirement of non-clinical pharmacokinetic and pharmacodynamic study, was developed to determine the concentration of rh-anti-CD20zumAb in plasma samples of rhesus monkeys. A chloramine-T method was established to prepare 125I-rh-anti-CD20zumAb. The method of radiolabeled tracer coupled with SHPLC and TCA precipitation was applied to evaluate the biodistribution, metabolism and excretion in rhesus monkeys.RESULTS AND CONCLUSIONS:1. After a single vd administration of rh-anti-CD20zumAb at different dosage levels (10, 30, 100 mg·kg-1) in rhesus monkeys, the ratio of the maximum concentration (Cmax) (1:2.2:7.5) and the ratio of the area under concentration-time curve (AUC) (1:2.5:4.9) exhibited a non-parallel manner depending on different dosage levels, which indicated that the pharmacokinetics of the rh-anti-CD20zumAb behaved a nonlinear characteristic within the dosage range studied. 2. After vd administration at 30 mg·kg-1 for 4 consecutive weeks (once weekly), the factor of accumulation is 1.8±0.5(P<0.05). It suggested that there was accumulation tendency after multiple doses via the given dosage, route and the times. 3. The mean quantity of CD20+ B lymphocyte cell was 23.8 %±7.7 %. The quantity of CD20+ B lymphocyte cell decreased promptly to 0.2 % after adminstration. Except low dose group, the quantity of CD20+ B lymphocyte cell did not recover to normal after 20 days, which indicated that rh-anti-CD20zumAb had a prompt and long-term effect on CD20+ B lymphocyte cell at all dose levels. 4. After a single vd administration of 125I-rh-anti-CD20zumAb at 10 mg·kg-1 in rhesus monkeys, distributed predominantly in serum, kidney, spleen, liver, lung, bone marrow and heart, et al. There was high concentration of 125I-rh-anti-CD20zumAb in bone marrow and spleen, which could indicate its targeting distribution. 5. The radioactivity was comparatively low in brain, suggested the drug could hardly get across the blood-brain barrier. 6. The radioactivity was excreted mainly via the urinary system, and a little part was excreted via feces. 7. There was no remarkable plasma protein binding of 125I-rh-anti- CD20zumAb was observed in the SHPLC behavior in 4℃for 12h.