Objective: To construct a physiologically-based pharmacokinetic (PBPK) model for predicting nilotinib pharmacokinetics (PK) in plasma and cerebrospinal fluid (CSF); and, to compare model-predicted serum and CSF exposures to those observed in the NILO-PD clinical trial.

Background: Nilotinib is a c-Abl inhibitor that has been investigated in two phase 2 clinical trials as a potential disease modifying agent for Parkinson’s disease (PD). The NILO-PD clinical trial randomized 76 participants with moderate to advanced PD to either once daily nilotinib 150mg, 300mg, or placebo with the objective to assess safety and tolerability. Exploratory outcomes of serum and CSF concentrations of nilotinib were measured and demonstrated average CSF-to-serum ratios of 0.002 to 0.003 for the 150mg and 300mg dosage groups, respectively. Additional PK samples will be used to develop and validate a PBPK model that simulates and predicts the full nilotinib PK profile in humans.

Method: Pre-dose trough serum samples for measurement of nilotinib concentrations were collected 14, 30, and 90 days post-baseline visit. Randomly collected samples relative to dose were collected 60, 120, 150, and 180 days post baseline visit. Paired serum and CSF samples 2 hours post-dose were also collected at the 90-day visit. The 4Brain model in the Simcyp Simulator® will be used to construct a whole-body PBPK model of nilotinib to predict concentrations in serum, spinal CSF, cranial CSF, and brain mass. Simulations will be performed to match the NILO-PD cohort on demographics (age, sex) and study design (dosing regimen, sampling plan, size). The simulated serum and spinal CSF concentrations will be compared to the clinical samples observed from NILO-PD.

Results: Among the 150mg group (N=25), the geometric mean [95% CI] serum trough concentrations of nilotinib at days 14 (n=18), 30 (n=20), and 90 (n=16) were 177 [123, 255], 185 [133, 258], and 195 [123, 309] ng/mL, respectively. Corresponding serum trough concentrations for the 300mg group (N=26) at days 14 (n=22), 30 (n=21), and 90 (n=21) were 214 [173, 264], 279 [214, 365], and 326 [247, 431] ng/mL, respectively. The remaining nilotinib concentration measurements will be summarized and reported for comparison against PBPK-simulated concentrations.

Conclusion: Development of a PBPK model for nilotinib will be useful in exploring and confirming its CNS kinetics in the PD population.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/physiologically-based-pharmacokinetic-modeling-of-nilotinib-to-determine-serum-cerebrospinal-fluid-and-brain-exposures/