Gestation stage‐dependent changes in monoclonal antibody pharmacokinetics and function during rat pregnancy

Abstract

We studied monoclonal IgG1 antibody (mAb) pharmacokinetics (PCKN) and in vivo function in pregnant rats from gestation day (GD) 8 to GD21 (1–2 day antepartum). On GD8, pregnant rats (n=4) received an iv‐bolus dose of 15 mg/kg of anti‐phencyclidine mAb6B5 or anti‐methamphetamine mAb6H4 along with a [3H]‐mAb tracer. PCKN analysis of serum mAb concentration‐time data showed significant (p<0.001) gestation stage‐dependent changes in terminal elimination half‐life (t1/2λz) for both mAb's. From GD9 to ~GD15‐GD18, the t1/2λz of mAb6B5 and mAb6H4 were 3.6 ± 0.4 and 3.1 ± 0.3 days, respectively. However, between ~GD15‐GD18, the t1/2λz of these mAb's abruptly decreased to 1.0 ± 0.1 and 1.1 ± 0.2 days, respectively. When 15 mg/kg mAb6B5 was dosed on GD15, we found a similarly decreased late‐gestation t1/2λz of 1.4 ± 0.2 days. Importantly, IgG1 PCKN was dose‐independent, since a 90 mg/kg mAb6B5 dose on GD8 demonstrated the same PCKN profile from GD8‐GD21 as the 15 mg/kg mAb6B5 dose. In vivo mAb6B5 serum phencyclidine (PCP) binding in the presence of infused PCP also showed decreased mAb function starting at ~GD15. We observed that the dramatic decrease in mAb t1/2λz and function always coincided with the start of an accelerated dam weight gain. These findings represent an important step in understanding mAb PCKN and function during pregnancy. (Funded by NIDA DA07610, Kirschstien NRSA DA24522, and a GlaxoSmithKline fellowship).