Effect of ritonavir-induced cytochrome P450 3A4 inhibition on plasma fentanyl concentrations during patient-controlled epidural labor analgesia: a pharmacokinetic simulation.

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BACKGROUND: Ritonavir inhibition of cytochrome P450 3A4 decreases the elimination clearance of fentanyl by 67%. We used a pharmacokinetic model developed from published data to simulate the effect of sample patient-controlled epidural labor analgesic regimens on plasma fentanyl concentrations in the absence and presence of ritonavir-induced cytochrome P450 3A4 inhibition. METHODS: Fentanyl absorption from the epidural space was modeled using tanks-in-series delay elements. Systemic fentanyl disposition was described using a three-compartment pharmacokinetic model. Parameters for epidural drug absorption were estimated by fitting the model to reported plasma fentanyl concentrations measured after epidural administration. The validity of the model was assessed by comparing predicted plasma concentrations after epidural administration to published data. The effect of ritonavir was modeled as a 67% decrease in fentanyl elimination clearance. Plasma fentanyl concentrations were simulated for six sample patient-controlled epidural labor analgesic regimens over 24 h using ritonavir and control models. Simulated data were analyzed to determine if plasma fentanyl concentrations producing a 50% decrease in minute ventilation (6.1 ng/mL) were achieved. RESULTS: Simulated plasma fentanyl concentrations in the ritonavir group were higher than those in the control group for all sample labor analgesic regimens. Maximum plasma fentanyl concentrations were 1.8 ng/mL and 3.4 ng/mL for the normal and ritonavir simulations, respectively, and did not reach concentrations associated with 50% decrease in minute ventilation. CONCLUSION: Our model predicts that even with maximal clinical dosing regimens of epidural fentanyl over 24 h, ritonavir-induced cytochrome P450 3A4 inhibition is unlikely to produce plasma fentanyl concentrations associated with a decrease in minute ventilation.





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Cambic, CR, MJ Avram, DK Gupta and CA Wong (2014). Effect of ritonavir-induced cytochrome P450 3A4 inhibition on plasma fentanyl concentrations during patient-controlled epidural labor analgesia: a pharmacokinetic simulation. Int J Obstet Anesth, 23(1). pp. 45–51. 10.1016/j.ijoa.2013.08.011 Retrieved from https://hdl.handle.net/10161/9487.

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Dhanesh Kumar Gupta

Professor of Anesthesiology

The overall theme of my research is the application of clinical pharmacology tools to the individualization of the care of high-risk surgical patients, especially those undergoing neurosurgical procedures.  Current research focuses on creating pharmacokinetic-pharmacodynamic models to allow simulation of dose-concentration-effect relationships that will result in reduced toxicity while maximizing efficacy of intravenous opioids and hypnotics. The perioperative period is a time when patients are exposed to a multitude of drugs from a different classes, some of which may attenuate while others may augment the deleterious cascade of events that starts in the operating room and result in worse neuro-oncologic, neurovascular, or pain outcomes, even after the perioperative medication has been discontinued.  Analytical techniques for perioperative “big data” have not been combined with the clinical pharmacology toolbox to create dose-response models that can help optimize perioperative care. Through collaboration with pharmacometricians and informaticians, care paths can be developed in an iterative fashion to expose the innards of the perioperative black box.

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