Population pharmacokinetic-pharmacodynamic modelling of liquid and controlled-release formulations of oxycodone in healthy volunteers
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Population pharmacokinetic-pharmacodynamic modelling of liquid and controlled-release formulations of oxycodone in healthy volunteers. / Ladebo, Louise; Foster, David J.R.; Abuhelwa, Ahmad Y.; Upton, Richard N.; Kongstad, Kenneth T.; Drewes, Asbjørn M.; Christrup, Lona L.; Olesen, Anne E.
In: Basic & Clinical Pharmacology & Toxicology, Vol. 126, No. 3, 2020, p. 263-276.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Population pharmacokinetic-pharmacodynamic modelling of liquid and controlled-release formulations of oxycodone in healthy volunteers
AU - Ladebo, Louise
AU - Foster, David J.R.
AU - Abuhelwa, Ahmad Y.
AU - Upton, Richard N.
AU - Kongstad, Kenneth T.
AU - Drewes, Asbjørn M.
AU - Christrup, Lona L.
AU - Olesen, Anne E.
PY - 2020
Y1 - 2020
N2 - 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 (kaCR = 0.19 hour-1) compared to the oral solution (kaSOL = 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 Emax 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.
AB - 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 (kaCR = 0.19 hour-1) compared to the oral solution (kaSOL = 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 Emax 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.
KW - Analgesia
KW - Oral controlled-release formulation
KW - Oral solution
KW - Oxycodone
KW - Pharmacokinetic-pharmacodynamic modelling
U2 - 10.1111/bcpt.13330
DO - 10.1111/bcpt.13330
M3 - Journal article
C2 - 31597014
AN - SCOPUS:85074670556
VL - 126
SP - 263
EP - 276
JO - Basic and Clinical Pharmacology and Toxicology
JF - Basic and Clinical Pharmacology and Toxicology
SN - 1742-7835
IS - 3
ER -
ID: 234564283