Effect of ritonavir-induced cytochrome P450 3A4 inhibition on plasma fentanyl concentrations: a pharmacokinetic simulation

15 Background: Ritonavir inhibition of cytochrome p450 3A4 decreases the elimination 16 clearance of fentanyl by 67%. We used a pharmacokinetic model developed from published 17 data to simulate the effect of sample patient-controlled epidural labor analgesic regimens on 18 plasma fentanyl concentrations in the absence and presence of ritonavir-induced cytochrome 19 p450 3A4 inhibition. 20 Methods: Fentanyl absorption from the epidural space was modeled using tanks-in-series 21 delay elements. Systemic fentanyl disposition was described using a three-compartment 22 pharmacokinetic model. Parameters for epidural drug absorption were estimated by fitting the 23 model to reported plasma fentanyl concentrations measured after epidural administration. The 24 validity of the model was assessed by comparing predicted plasma concentrations after 25 epidural administration to published data. The effect of ritonavir was modeled as a 67% 26 decrease in fentanyl elimination clearance. Plasma fentanyl concentrations were simulated for 27 six sample patient-controlled epidural labor analgesic regimens over 24 h using ritonavir and 28 control models. Simulated data were analyzed to determine if plasma fentanyl concentrations 29 producing a 50% decrease in minute ventilation (6.1 ng/mL) were achieved. 30 Results: Simulated plasma fentanyl concentrations in the ritonavir group were higher than 31 those in the control group for all sample labor analgesic regimens. Maximum plasma fentanyl 32 concentrations were 1.8 ng/mL and 3.4 ng/mL for the normal and ritonavir simulations, 33 respectively, and did not reach concentrations associated with 50% decrease in minute 34 ventilation. 35 Conclusion: Our model predicts that even with maximal clinical dosing regimens of epidural 36 fentanyl over 24 h, ritonavir-induced cytochrome p450 3A4 inhibition is unlikely to produce 37 plasma fentanyl concentrations associated with a decrease in minute ventilation. 38 39