A Model-Based Approach to Predicting the Human Pharmacokinetics of a Monoclonal Antibody Exhibiting Target-Mediated Drug Disposition

Abstract

In the drug discovery and development setting, the ability to accurately predict the human pharmacokinetics (PK) of a candidate compound from preclinical data is critical for informing the effective design of the first-in-human trial. PK prediction is especially challenging for monoclonal antibodies exhibiting nonlinear PK attributed to target-mediated drug disposition (TMDD). Here, we present a model-based method for predicting the PK of PF-03446962, an IgG2 antibody directed against human ALK1 (activin receptor-like kinase 1) receptor. Systems parameters as determined experimentally or obtained from the literature, such as binding affinity (k on and k off ), internalization of the drug-target complex (k int ), target degradation rate (k deg ), and target abundance (R 0 ), were directly integrated into the modeling and prediction. NONMEM 7 was used to model monkey PK data and simulate human PK profiles based on the construct of a TMDD model using a population-based approach. As validated by actual patient data from a phase I study, the human PK of PF-03446962 were predicted within 1-to 2-fold of observations. Whereas traditional approaches fail, this approach successfully predicted the human PK of a monoclonal antibody exhibiting nonlinearity because of TMDD.

A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors

“…Telangiectasia, which is associated with mutations in the ALK-1 gene in patients affected by HHT type 2, was observed in approximately 9% of patients, and considered to be treatment-related in approximately 7%, suggesting target engagement and in vivo inhibition of ALK-1 by PF-03446962 (9)(10)(11). A similar finding of treatment-related telangiectasia has been reported in clinical studies of an ALK-1 receptor fusion protein (dalantercept) and an endoglin-neutralizing antibody (TRC105) in patients with advanced cancer (13)(14)(15)(16).…”

“…It has been shown in preclinical studies to selectively block binding of the ALK-1 ligands BMP-9 and TGFb to ALK-1, and to inhibit recruitment of the coreceptor endoglin into the ALK-1 angiogenesis-signaling complex (10)(11)(12). PF-03446962 demonstrated antiangiogenic activity in human xenograft tumor models (12).…”

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

“…To predict human PK of antibodies that undergo TMDD, species differences of target expression levels and turnover as well as antibody interaction with target need to be considered. Scale up of the target-dependent component of antibody PK has been tackled with varying degrees of success using TMDD 7 , 8 and Michaelis-Menten (MM) 9 non-linear PK models. In both cases, appropriate scale up of the parameters that describe the PK non-linearity is critical to capture the differences across species.…”

Simulation of Monoclonal Antibody Pharmacokinetics in HumansUsing a Minimal Physiologically Based Model

“…This was chosen as an example as the values used to define the parameters for the TMDD model were largely derived from in vitro data. The parameters used to define the binding to target and elimination of the drug-target complex were taken from Luu et al (24) ; k int = 0.1821 h −1 ; CV =25% on each parameter) as were the parameters describing the level of ALK-1 (R max = 0.00174 μM; k deg =0.223 h −1 ; CV=20% on each parameter), the affinity to FcRn and CL cat were assumed to be the same as those of endogenous IgG (0.728 μM; CV=25% and 0.0175 L/h; CV=25%), respectively.…”