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Population pharmacokinetic‐pharmacodynamic modelling of liquid and controlled‐release formulations of oxycodone in healthy volunteers
Author(s) -
Ladebo Louise,
Foster David J. R.,
Abuhelwa Ahmad Y.,
Upton Richard N.,
Kongstad Kenneth T.,
Drewes Asbjørn M.,
Christrup Lona L.,
Olesen Anne E.
Publication year - 2020
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13330
Subject(s) - oxycodone , pharmacokinetics , pharmacodynamics , crossover study , absorption (acoustics) , pharmacology , opioid , anesthesia , medicine , population , immediate release , materials science , receptor , alternative medicine , environmental health , pathology , composite material , placebo
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.