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PBPK Modeling of Tizanidine Systemic Exposure by CYP1A2 Modulation: Impact of DDIs & Smoking


This webinar was presented on 2021 年 6 月 30 日 by David R. Taft, Ph.D. Professor, Pharmaceutics, Long Island University, NY, USA.

Here is a summary of his presentation:

• Tizanidine is an alpha2-adrenergic agonist, used to treat spasticity associated with multiple sclerosis and spinal injury. Tizanidine is primarily metabolized by CYP1A2 and is considered a sensitive index substrate for this enzyme.

• The physiologically based pharmacokinetic (PBPK) modeling platform Simcyp® was used to evaluate the impact of CYP1A2 modulation on tizanidine exposure through drug-drug interactions (DDIs) and host-dependent habits (cigarette smoking).

• A PBPK model was developed to predict tizanidine disposition in healthy volunteers following oral administration. The model was verified based on agreement between model-simulated and clinically observed systemic exposure metrics (Cmax, AUC).

• The model was then used to carry-out DDI simulations to predict alterations in tizanidine systemic exposure when co-administered with various CYP1A2 perpetrators including competitive inhibitor (fluvoxamine), a mechanism-based inhibitor (rofecoxib), and an inducer (rifampin). Additional simulations were performed to evaluate the impact of cigarette smoking on systemic exposure.

• Under each scenario, the PBPK model was able to capture the observed fold changes in tizanidine Cmax and AUC when coadministered with CYP1A2 inhibitors or inducers.

• These results supplement the available research findings in the literature on PBPK predictions of drug-drug interactions and illustrate its potential application in drug development, specifically to support product labeling.

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