Predicting Method for the Human Plasma Concentration-Time Profile of a Monoclonal Antibody from
the Half-Life of Non-human Primates
G. Nakamura, M. Kato, K. Yamaguchi, M. Nagayasu, T. Nambu, T. Nemoto, K. Ozeki, M. Ishigai
Chugai Pharmaceutical Co., Ltd.
Purpose
Prediction about human plasma concentration–time profile is an important part of drug development, especially prior to first-in-human
clinical studies. In this study, we focused on predicting linear elimination because of the difficulty and complexity of non-linear
elimination. A novel method (half-life method) was developed to predict the human plasma concentration–time profile of a
monoclonal antibody (mAb) after intravenous (IV) and subcutaneous (SC) administration, using human geometric means of
pharmacokinetics (PK) parameters and the half-life of non-human primates (NHP).
Methods
The human PK parameters of mAbs in published data were collected and analyzed to discover whether parameters extrapolated from
NHP were needed to predict the human plasma concentration–time profile after IV and SC dosing. The main search objectives were
therapeutic mAbs approved by FDA (Food and Drug Administration, USA) or PMDA (Pharmaceutical and Medical Devices Agency,
Japan) up to the end of 2015. The serum/plasma mean concentration–time profiles after IV administration were analyzed by the twocompartment model.
Results
In the data collected in this study, mAbs had bi-phased elimination decay after IV dosing in human, so two-compartment model
analysis was conducted, which gave CV values for human V1 and Vdss of about 20%. AUCinf was mainly covered by AUCβ in human
after IV dosing, and the contribution percentage to AUCinf exceeded 90%. These PK features were common in human and NHP. With
SC dosing, mAbs were absorbed well from the SC injection site with values for F within the range of 0.511–0.800. Human Ka of
mAbs were centralized to the geometric mean value. These results indicated that to predict the human plasma concentration–time
profile, V1, Vdss, Ka, and F parameters did not need to be extrapolated from NHP values. The half-life method using only NHP t1/2β
succeeded in obtaining estimations comparable to those obtained by two-compartment model analysis with allometric scaling, when
predicting the human plasma concentration–time profile.
Conclusion
We developed a half-life method that uses only t1/2β of NHP to predict the PK of mAbs in human. This method could predict the
human plasma concentration–time profile not only after IV, but also after SC dosing. Moreover, the accuracy of this half-life method
was comparable to that of the conventional methods.