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Handling missed dose of riluzole by population pharmacokinetic model informed remedial regimen
Changlong Liu1, Qing Tang2,3, Lingyan Yu2,4
1Department of Pharmacy, Hangzhou Linping Hospital of Traditional Chinese Medicine, Hangzhou, China.
Background:
Patients with amyotrophic lateral sclerosis (ALS) frequently exhibit nonadherence characterized by delayed or missed doses while taking riluzole. This study aimed to provide a population pharmacokinetic (PPK) model informed individualized remedial regimens for patients who experience delayed or missed doses of riluzole.
Methods:
A PPK model for riluzole was developed via a nonlinear mixed-effect modeling approach based on 3,024 concentration-time points from 72 subjects. The final model was validated by multiple methods. Six remedial regimens for missed doses were simulated for concentration-time profiles under different scenarios, and the optimal remedial regimen was selected based on the least time of concentration beyond the normal range.
Results:
The PPK model of riluzole was best described with a two-compartment model with body weight as a covariate of peripheral distribution volume. The typical values of CL/F, Vc/F, Vp/F and Q were 67 L/h, 242 L, 376 L and 33.1 L/h, respectively. The model was showed acceptable performance by goodness-of-fit, visual predictive check, bootstrap analysis and normalized distribution prediction errors. Model-based remedial regimens for different missed scenarios were proposed.
Conclusion:
A riluzole PPK model was developed and internally evaluated using multiple diagnostic approaches. Model-based remedial dosing strategies for different missed-dose scenarios were identified based on predefined PK criteria and Monte Carlo simulations. These exploratory strategies provide quantitative insights into riluzole exposure during nonadherent dosing conditions.
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