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

Jogiraju, Vamshi Krishna; Heimbach, Tycho; Toderika, Yuliana; Taft, David R.

doi:10.1016/j.dmpk.2020.100375

Cited by 7 publications

(3 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the inhibitor side, the simulated exposure of ciprofloxacin was reasonably consistent with the observed data from the ciprofloxacin-tizanidine DDI study (predicted AUC of 11.4 mg×h/l versus observed AUC of 7.8 mg×h/l). The ciprofloxacin model, as a CYP1A2 competitive inhibitor, was previously verified using independent clinical DDIs with a range of other CYP1A2 substrates (Jogiraju et al, 2021). Taken together, the evaluation showed that the underprediction of AUC ratios by the WSM was not due to the aforementioned common sources of predictive error.…”

Section: Discussionmentioning

confidence: 82%

“…The PBPK models for ciprofloxacin, fluvoxamine, and rifampicin were the default library files within the Simcyp Simulator. The PBPK model for rofecoxib was adopted from the literature (Jogiraju et al, 2021). In this study, all of the perpetrator PBPK models were developed using the WSM, and the effect of using the PerMCL model for the perpetrators on the predicted DDIs, if any, was anticipated to be minimal.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Understanding Interindividual Variability in the Drug Interaction of a Highly Extracted CYP1A2 Substrate Tizanidine: Application of a Permeability-Limited Multicompartment Liver Model in a Population Based Physiologically Based Pharmacokinetic Framework

Zhang¹,

Fisher²,

Gardner³

et al. 2022

Drug Metab Dispos

View full text Add to dashboard Cite

Tizanidine, a centrally acting skeletal muscle relaxant, is predominantly metabolized by CYP1A2 and undergoes extensive hepatic first-pass metabolism after oral administration. As a highly extracted drug, the systemic exposure to tizanidine exhibits considerable interindividual variability and is altered substantially when coadministered with CYP1A2 inhibitors or inducers. The aim of the current study was to compare the performance of a permeabilitylimited multicompartment liver (PerMCL) model, which operates as an approximation of the dispersion model, and the well stirred model (WSM) for predicting tizanidine drug-drug interactions (DDIs). Physiologically based pharmacokinetic models were developed for tizanidine, incorporating the PerMCL model and the WSM, respectively, to simulate the interaction of tizanidine with a range of CYP1A2 inhibitors and inducers. Whereas the WSM showed a tendency to underpredict the fold change of tizanidine area under the plasma concentration-time curve (AUC ratio) in the presence of perpetrators, the use of PerMCL model increased precision (absolute average-fold error: 1.32-1.42 versus 1.58) and decreased bias (average-fold error: 0.97-1.25 versus 0.63) for the predictions of mean AUC ratios as compared with the WSM. The PerMCL model captured the observed range of individual AUC ratios of tizanidine as well as the correlation between individual AUC ratios and CYP1A2 activities without interactions, whereas the WSM was not able to capture these. The results demonstrate the advantage of using the PerMCL model over the WSM in predicting the magnitude and interindividual variability of DDIs for a highly extracted sensitive substrate tizanidine. SIGNIFICANCE STATEMENTThis study demonstrates the advantages of the PerMCL model, which operates as an approximation of the dispersion model, in mitigating the tendency of the WSM to underpredict the magnitude and variability of DDIs of a highly extracted CYP1A2 substrate tizanidine when it is administered with CYP1A2 inhibitors or inducers. The physiologically based pharmacokinetic modeling approach described herein is valuable to the understanding of drug interactions of highly extracted substrates and the source of its interindividual variability. ABBREVIATIONS: AAFE, absolute average-fold error; AFE, average-fold error; AUC, area under the plasma concentration-time curve; CL int , intrinsic clearance; CL int, H , hepatic intrinsic clearance; CL PD , passive diffusion clearance; CL PD, in vitro , passive diffusion clearance measured in vitro; CL PO , oral clearance; DDI, drug-drug interaction; DM, dispersion model; D N , dispersion number; E H , hepatic extraction ratio; EW, extracellular water; fm, fraction of the systemic clearance of a drug mediated by a given enzyme; IW, intracellular water; PBPK, physiologically based pharmacokinetic; PerMCL, permeability-limited multicompartment liver; PK, pharmacokinetics; WSM, well stirred model.

show abstract

Section: Discussionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Understanding Interindividual Variability in the Drug Interaction of a Highly Extracted CYP1A2 Substrate Tizanidine: Application of a Permeability-Limited Multicompartment Liver Model in a Population Based Physiologically Based Pharmacokinetic Framework

Zhang¹,

Fisher²,

Gardner³

et al. 2022

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…For heavy smokers (>20 cigarettes per day), the dose of tizanidine may need to be higher than the average dose because the simulated C max and AUC are reduced by about 50% compared to nonsmokers. 72 Tizanidine is primarily metabolized by CYP1A2, so it is necessary to explore the effect of CYP1A2 genetic polymorphisms on the optimal dosing of tizanidine.…”

Section: Discussionmentioning

confidence: 99%

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations

Zhu,

Wang,

Zhou

2024

JPR

View full text Add to dashboard Cite

Background Skeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria ® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration. Methods Relevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase. Results Tizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer’s disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel. Conclusion Tizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.

show abstract

Risk of tizanidine-induced adverse events after concomitant exposure to ciprofloxacin: A cohort study in the U.S.

Giannouchos¹,

Gómez-Lumbreras

Malone

2022

The American Journal of Emergency Medicine

View full text Add to dashboard Cite

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

Cited by 7 publications

References 36 publications

Understanding Interindividual Variability in the Drug Interaction of a Highly Extracted CYP1A2 Substrate Tizanidine: Application of a Permeability-Limited Multicompartment Liver Model in a Population Based Physiologically Based Pharmacokinetic Framework

Understanding Interindividual Variability in the Drug Interaction of a Highly Extracted CYP1A2 Substrate Tizanidine: Application of a Permeability-Limited Multicompartment Liver Model in a Population Based Physiologically Based Pharmacokinetic Framework

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations

Risk of tizanidine-induced adverse events after concomitant exposure to ciprofloxacin: A cohort study in the U.S.

Contact Info

Product

Resources

About