Application of physiologically based pharmacokinetic modeling to predict drug-drug interactions between Rocuronium/Propofol/Paracetamol and Lidocaine

Abstract

Preoperative, intraoperative, and postoperative phases are all included in the perioperative period and are essential to offering patients comprehensive care. To ensure a healthier environment for patients throughout the procedure, this process involves mental and physical preparation, preliminary studies for a successful surgery, and recovery monitoring to prevent complications. Opioids and other drugs are frequently used in perioperative care to effectively manage pain. However, these drugs can lead to drug-drug interactions (DDIs), where the combination of drugs may result in adverse effects, altering their pharmacokinetics or pharmacodynamics and leading to adverse drug reactions (ADRs). ADRs are serious clinical issues that lead to morbidity, mortality, and higher medical expenses. Electronic databases such as GastroPlus® PBBM / PBPK have been developed to evaluate potentially harmful DDIs as medical science progresses. During the intraoperative phase of anesthesia administration, anesthetists frequently face these interactions and must make well-informed therapeutic decisions. The desired effects of anesthesia frequently call for the combination of one or more drugs, which means that dose adjustments and management must be accomplished carefully. The objective of this thesis was to examine the effects of three drugs-rocuronium, propofol, and paracetamol-used in combination with lidocaine and to evaluate the efficacy of these combinations. We focused on the CYP-mediated metabolism of lidocaine, exploring these drugs due to their common clinical use at CHUSJ and the lack of existing literature on their combined effects. Physiologically based pharmacokinetic (PBPK) modeling and an in vitro model using Hep G2 cells were used to assess the CYP-mediated drug interactions. To investigate cell viability with each drug alone and in combination, first, a Hep G2 cell culture was created, and then the MTT test to determine cell viability. After that, we conducted a thorough analysis using liquid chromatography-mass spectrometry (LC-MS), for detailed analysis. After that, we created, validated, and used a PBPK model to simulate DDIs, specifically predicting how LIDO would interact with rocuronium, propofol, and paracetamol. The predictive performance of PBPK for CYP enzyme-mediated metabolic DDIs is well-established, and many PBPK simulations have been submitted to regulatory agencies and accepted as the basis for dose adjustment on drug labels. Biopharmaceutical parameters for all drugs and metabolites were sourced from literature or predicted by ADMET Predictor(r) (Simulations Plus, Inc.). The results obtained demonstrated that the combination of propofol and rocuronium with lidocaine demonstrated notable toxicity in the cellular model, and according to the PBPK model studies, depending on the dose and how the drug was combined with other drugs, some covariates significantly affected the pharmacokinetics of lidocaine. The ultimate goal of this research is to advance the field towards a precision medicine model customized for each patient by changing the clinical use paradigm of lidocaine in combination with other drugs. By going beyond the "one-size-fits-all" method of anesthetic management, this strategy seeks to provide perioperative care that is safer and more efficient.