Inferring Target Occupancy from Fitting Nonlinear-PK Data with Mechanistic PKRO Model for Pembrolizumab


Purpose: Pembrolizumab (Pembro), an anti-PD-1 antibody, has been approved for several cancer indications at 200 mg or 2 mg/kg IV every 3 weeks (Q3W). Understanding the percent target receptor occupancy (RO) for PD-1 at this approved dose can help with dose selection for other anti-PD-1 drugs in development. However, RO can be challenging to determine through direct experimental measurements. A mechanistic PKRO model was developed to fit to Pembro phase 1 PK data and was then used to predict RO at 2 mg/kg IV dosing Q3W.

Methods: A mechanistic PKRO model describes linear clearance of Pembro, tissue distribution of Pembro, binding to PD-1, binding to soluble PD-1 (sPD-1) and clearance of drug-PD-1 complex, clearance of drug-sPD-1 complex as well as drug distribution to tumor and binding to PD-1 in the tumor compartment. Binding between Pembro and PD-1 was fixed to 29 pM (Pembro BLA, Pharmacology Review) and half-life of internalization of drug-PD-1 complex was set to 2 hours. 

Results: Since a wide range of sPD-1 concentration has been reported, different sPD-1 concentration was used to fit to the PK data.  The model predicted PD-1 expression level in circulation to be approximately 10.8 pM with no soluble PD-1. In the presence of soluble PD-1, PD-1 expression is predicted to be higher to capture the non-linear PK. The model was then used to predict RO at 2 mg/kg IV dosing Q3W and > 98% RO was predicted in the tumor compartment with a range of sPD-1 concentrations from 0 to 3000 pg/mL tested. The impact of Kd and drug-PD-1 turnover rate on predicted RO was explored. When either of the parameters was varied by 10-fold higher or lower from its nominal value, the model still predicted greater than 90% RO at 2 mg/kg dose.

Conclusion: A mechanistic PKRO model was built to capture Pembro phase I PK data and then predicted near complete PD-1 target receptor occupancy at the approved dose. This approach with expanded model scope has the potential to be used to inform dose selection for other anti-PD-1, or I/O therapeutics, as a single therapy or in combination.

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