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THE EFFECT OF RITONAVIR ADMINISTRATION ON PLASMA FENTANYL LEVELS DURING EPIDURAL ADMINISTRATION: A PHARMACOKINETIC SIMULATION
Abstract Number: 191
Abstract Type: Original Research
Introduction: Ritonavir, a protease inhibitor that decreases the rate of vertical transmission of HIV, inhibits the CYP3A4 enzyme. Fentanyl, an opioid used in epidural infusions for labor analgesia, is metabolized primarily by CYP3A4. An earlier study reported that ritonavir reduces the elimination clearance of IV fentanyl by 67% in healthy volunteers, but did not provide a detailed pharmacokinetic model.1 We developed a model to simulate the effect of 8 epidural fentanyl regimens on plasma fentanyl levels in a normal individual (control) and an individual on ritonavir.
Methods: Three-compartmental systemic fentanyl pharmacokinetics were used to describe fentanyl disposition after absorption from the epidural space.2 The most detailed pharmacokinetic description of drug absorption from the epidural space is of the biphasic absorption of ropivacaine, which has similar physiochemical properties with fentanyl.3 Biphasic fentanyl absorption parameters were estimated by modeling the plasma fentanyl concentration versus time relationship observed in the first 20 min after epidural administration of 80μg fentanyl in a prior study.4 Drug absorption was described using tanks-in-series delay elements to characterize the non-instantaneous appearance of the drug in the body. The validity of the resulting absorption-disposition model was assessed by comparing predicted plasma fentanyl concentrations after epidural fentanyl bolus and infusion dosing reported in a previous study.5 Since the model estimated these data, it was used to simulate the effect on plasma fentanyl levels in the control and ritonavir groups receiving 8 epidural regimens of either 2μg/ml or 3μg/ml of fentanyl with or without an initial 100μg fentanyl bolus.
Results: Plasma fentanyl concentrations for both groups at the end of 2 hours of epidural administration for each of the epidural regimens are listed in the Table. The mean difference in plasma fentanyl concentrations between groups was 0.22 +/- 0.06ng/ml, with higher concentrations in the ritonavir group.
Discussion: We developed a pharmacokinetic model that demonstrated a small increase in plasma fentanyl levels in 8 epidurally administered fentanyl regimens for patients on chronic ritonavir therapy. However, the clinical effect of this difference is likely insignificant.
1. Anesthesiology 1999;91:681-5
2. Anesthesiology 2008;109:664-74
3. Clin Pharmacol Ther 2008:153-7
4. Anaesthesia 1983;38:937-42
5. Anesth Analg 2003;97:1428-38