Abstract:
Cynomolgus monkeys and human FcRn transgenic mice are generally used for pharmacokinetic predictions of therapeutic monoclonal antibodies (mAbs). In the present study, the application of the common marmoset, a small nonhuman primate, as a potential animal model for prediction was evaluated for the first time.Canakinumab, adalimumab, and bevacizumab, which exhibited linear pharmacokinetics in humans, were selected as the model compounds. Marmoset pharmacokinetic data were reportedly available only for canakinumab, and those for adalimumab and bevacizumab were acquired in-house.Four pharmacokinetic parameters for a two-compartment model (i.e. clearance and volume of distribution in the central and peripheral compartments) in marmosets were extrapolated to the values in humans with allometric scaling using the average exponents of the three mAbs. As a result, the observed human serum concentration-time curves of the three mAbs following intravenous administration and those of canakinumab and adalimumab following subcutaneous injections (with an assumed absorption rate constant and bioavailability) were reasonably predicted.Although further prediction studies using a sufficient number of other mAbs are necessary to evaluate the versatility of this model, the findings indicate that marmosets can be an alternative to preceding animals for human pharmacokinetic predictions of therapeutic mAbs.
摘要:
1.食蟹猴和人FcRn转基因小鼠通常用于治疗性单克隆抗体(mAb)的药代动力学预测。在本研究中,普通猕猴桃的应用,一个小型的非人类灵长类动物,作为预测的潜在动物模型进行了首次评估。Canakinumab,阿达木单抗,还有贝伐单抗,在人体中表现出线性药代动力学,被选为模型化合物。据报道,Marmoset药代动力学数据仅适用于canakinumab,阿达木单抗和贝伐单抗的患者是在家中获得的3.两室模型的四个药代动力学参数(即,使用三种mAbs的平均指数,用异速缩放比例将the猴的中央和外围区室的清除率和分布体积)外推至人类的值。因此,静脉内给药后观察到的三种mAb的人血清浓度-时间曲线以及皮下注射后的canakinumab和adalimumab的人血清浓度-时间曲线(假定的吸收速率常数和生物利用度)是合理预测的.尽管需要使用足够数量的其他mAb进行进一步的预测研究来评估该模型的多功能性,研究结果表明,对于治疗性单克隆抗体的人体药代动力学预测,马尾猴可以替代先前的动物.