Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration

ABSTRACT

Objectives: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration.

Methods: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package.

Results: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively.

Conclusion: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.

KEYWORDS:

• Oxycodone
• intravenous
• epidural
• population pharmacokinetics
• NONMEM
• central nervous system

Author Contributions

M.L.: conception and design, analysis and interpretation of the data, the drafting of the paper and revising it critically for intellectual content; P.P.: interpretation of the data; the drafting of the paper and revising it critically for intellectual content; H.K.: conception and design, interpretation of the data, the drafting of the paper and revising it critically for intellectual content; C.K.: analysis and interpretation of the data, revising the paper critically for intellectual content; V-P.R.: conception and design, analysis and interpretation of the data, revising the paper critically for intellectual content; P.V.: analysis and interpretation of the data, revising the paper critically for intellectual content; M.K.: principal investigator, conception and design, analysis and interpretation of the data, the final approval of the version to be published. All authors agree to be accountable for all aspects of the work.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Supplementary material

Supplementary data for this article can be accessed here.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Governmental VTR-fund, the Hospital District of Northern Savo, Kuopio, Finland, and Olvi Foundation, Iisalmi, Finland.