Clinical Pharmacologist Pfizer, Inc. San Diego, California, United States
Background: PF-06952229 is an orally administered small molecule inhibitor of the serine/threonine kinase receptor transforming growth factor beta receptor (TGFβR1). In a first-in-patient (FIP) study to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD), PF-06952229 was administered to previously treated patients with advanced solid tumors known to have high TGFβ signatures. The objective of this work is to describe the development of a population PK model for PF-06955529, and to evaluate the potential influence of patient demographics and baseline covariates on PK of PF-06952229. Methods: PF-06952229 was orally administered twice daily in a 7 days on / 7 days off schedule within a 28-day cycle regimen in doses ranging from 20 mg to 500 mg BID. The dataset included 724 plasma concentrations from 41 patients and was used to develop a population PK model of PF-06952229 using a nonlinear mixed-effects modeling approach. Covariates were evaluated on all parameters for influence on PK using stepwise covariate modeling, and included age, sex, race, bodyweight, administration with food, and administration with a proton pump inhibitor. Model fit was assessed by objective function value and goodness-of-fit diagnostics, and the model was validated using bootstrap analysis and visual predictive check. Results: A two-compartment model with first-order oral absorption (KA), relative oral bioavailability, and combined additive and proportional residual unexplained variability adequately described the PK of PF-06952229. PK was dose proportional and time independent. Covariate analysis identified administration of the drug with a high fat meal reduced the KA by 86%. Additionally, coadministration of the drug with a proton pump inhibitor was associated with a 42% decrease in relative oral bioavailability. No additional covariates tested were identified as statistically significant factors for their impact on PF-06952229 PK. Conclusion: Overall, the developed population PK model for PF-06952229 was able to characterize the data well. This model may provide utility for any future exposure response analyses with PF-06952229 as well as provide guidance for other TGFβR inhibitors in clinical development.
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