Physiologically based pharmacokinetic modeling of altered tizanidine systemic exposure by CYP1A2 modulation: Impact of drug-drug interactions and cigarette consumption.

Physiologically based pharmacokinetic modeling of altered tizanidine systemic exposure by CYP1A2 modulation: Impact of drug-drug interactions and cigarette consumption. Drug Metab Pharmacokinet. 2020 Dec 13;37:100375 Authors: Jogiraju VK, Heimbach T, Toderika Y, Taft DR Abstract 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 inhibitors (fluvoxamine, ciprofloxacin), 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...
Source: Drug Metabolism and Pharmacokinetics - Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research