AI Article Synopsis
- - The study focuses on SAF-189s, an advanced drug in clinical trials aimed at treating non-small cell lung cancer (NSCLC) that is positive for ALK and ROS1 mutations, using population pharmacokinetics (PopPK) to assess its safety and effectiveness.
- - Researchers analyzed plasma concentration data from 299 patients and 24 healthy individuals, considering various factors like age and prior treatments to understand how these influence the drug's effects and side effects.
- - Findings indicate that while higher doses (210 mg) resulted in more side effects like hyperglycemia and less tolerability, efficacy appeared to plateau at doses between 80-210 mg, suggesting no significant benefit from increasing the dose further.
Article Abstract
Objective: SAF-189s is a potent ALK/ROS1 inhibitor that is currently in clinical development for treating advanced ALK+/ROS1+ non-small cell lung cancer (NSCLC). Comprehensive population pharmacokinetics (PopPK) and exposure-response models were developed to evaluate the efficacy and safety of SAF-189s by integrating data from two clinical studies.
Methods: The PopPK model was developed using plasma concentration data collected from patients with ALK+/ROS1+ advanced NSCLC (n = 299) and healthy subjects (n = 24). The covariates (demographics, laboratory values, subject types, and concomitant medications) were evaluated to determine their potential influence on the between-patient variability in the pharmacokinetics of SAF-189s. Individual exposure values were then used to investigate the relationships with the efficacy endpoints (overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR)) and key safety endpoints (adverse events of interest).
Results: The final PopPK model of SAF-189s was described by a one-compartment model with delayed first-order absorption and time-dependent elimination by allowing the clearance to decrease stepwise over time. Age was included as a covariate for apparent clearance (CL/F), while prior anti-cancer therapy in ALK+ patients (ALKPOT) was included for apparent volume of distribution (V/F). There were no apparent exposure-response relationships for any of the efficacy endpoints at doses of 80-210 mg. The relationship between exposure and safety suggested that a higher steady-state exposure was associated with more frequent incidences of hyperglycemia and proteinuria; the 210-mg dose group was also less tolerated than the other low-dose groups.
Conclusion: PopPK and exposure-response models were developed for SAF-189s, and their results demonstrate that SAF-189s exposures are at the plateau of exposure-response for efficacy. The 210-mg dose group had a significantly higher safety risk, while the 160-mg dose group was well-tolerated. Thus, 160 mg of SAF-189s once daily was selected as the recommended phase III dose for the ALK+/ROS1+ or ROS1+ NSCLC patients.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286589 | PMC |
| http://dx.doi.org/10.3389/fphar.2024.1418549 | DOI Listing |
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