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.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.identifier

http://www.ncbi.nlm.nih.gov/pubmed/24333052

dc.identifier

S0959-289X(13)00122-2

dc.identifier.eissn

1532-3374

dc.identifier.uri

https://hdl.handle.net/10161/9487

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.orcid

Gupta, DK|0000-0001-9505-595X

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

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
CRC Fentanyl Ritonavir IJOA AOP.pdf
Size:
4.09 MB
Format:
Adobe Portable Document Format
Description:
Published version