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

dc.contributor.author Cambic, CR
dc.contributor.author Avram, MJ
dc.contributor.author Gupta, DK
dc.contributor.author Wong, CA
dc.coverage.spatial Netherlands
dc.date.accessioned 2015-02-20T20:43:22Z
dc.date.issued 2014-02
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/24333052
dc.identifier S0959-289X(13)00122-2
dc.identifier.uri https://hdl.handle.net/10161/9487
dc.description.abstract 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.
dc.language eng
dc.publisher Elsevier
dc.relation.ispartof Int J Obstet Anesth
dc.relation.isversionof 10.1016/j.ijoa.2013.08.011
dc.subject Analgesic techniques
dc.subject Extradural
dc.subject Obstetric Analgesia
dc.subject Pharmacokinetics fentanyl
dc.subject Ritonavir
dc.subject Analgesia, Epidural
dc.subject Analgesia, Patient-Controlled
dc.subject Analgesics, Opioid
dc.subject Cytochrome P-450 CYP3A
dc.subject Cytochrome P-450 CYP3A Inhibitors
dc.subject Drug Interactions
dc.subject Female
dc.subject Fentanyl
dc.subject HIV Protease Inhibitors
dc.subject Humans
dc.subject Pregnancy
dc.subject Ritonavir
dc.title Effect of ritonavir-induced cytochrome P450 3A4 inhibition on plasma fentanyl concentrations during patient-controlled epidural labor analgesia: a pharmacokinetic simulation.
dc.type Journal article
duke.contributor.id Gupta, DK|0667570
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/24333052
pubs.begin-page 45
pubs.end-page 51
pubs.issue 1
pubs.organisational-group Anesthesiology
pubs.organisational-group Anesthesiology, Neuroanesthesia
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group School of Medicine
pubs.publication-status Published
pubs.volume 23
dc.identifier.eissn 1532-3374
duke.contributor.orcid Gupta, DK|0000-0001-9505-595X


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