Population pharmacokinetic-pharmacodynamic modelling of liquid and controlled-release formulations of oxycodone in healthy volunteers

Louise Ladebo, David J R Foster, Ahmad Y Abuhelwa, Richard N Upton, Kenneth T Kongstad, Asbjørn M Drewes, Lona L Christrup, Anne E Olesen

Research output: Contribution to journalJournal articleResearchpeer-review


Oral controlled-release formulations are playing an ever-increasing role in opioid therapy; however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic-pharmacodynamics of two controlled-release tablet formulations and a liquid formulation of oxycodone in healthy, opioid-naïve volunteers, which can serve as a reference for future patient studies. A semi-double-blinded, three-way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled-release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post-dose. Oxycodone pharmacokinetics was best described by a two-compartment model with first-order absorption. The controlled-release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (k aCR = 0.19 hour -1 ) compared to the oral solution (k aSOL = 0.94 hour -1 ). Effects on pupil diameter were delayed relative to plasma (14 minutes half-life) for all formulations and were best described by a proportional E max model. The plasma concentration of oxycodone at half-maximum effect was lower in males (31.1 μg/L) compared to females (52.8 μg/L; P < .001). The absorption profile of controlled-release oxycodone formulations provided a prolonged onset and offset of action compared to oral solution oxycodone. The controlled-release formulations showed no differences in pharmacokinetic and pharmacodynamic parameters suggesting that both may be used interchangeably in human beings with normal gastrointestinal function.
Original languageEnglish
JournalBasic & Clinical Pharmacology & Toxicology
Issue number3
Pages (from-to)263-276
Publication statusPublished - Mar 2020
Externally publishedYes


  • Analgesia
  • Oral controlled-release formulation
  • Oral solution
  • Oxycodone
  • Pharmacokinetic-pharmacodynamic modelling
  • Double-Blind Method
  • Administration, Oral
  • Humans
  • Middle Aged
  • Half-Life
  • Male
  • Cross-Over Studies
  • Oxycodone/administration & dosage
  • Models, Biological
  • Adult
  • Female
  • Analgesics, Opioid/administration & dosage
  • Delayed-Action Preparations

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