Population pharmacokinetic modelling of morphine, gabapentin and their combination in the rat
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Population pharmacokinetic modelling of morphine, gabapentin and their combination in the rat. / Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Gabel-Jensen, Charlotte; Kreilgaard, Mads; Lund, Trine Meldgaard.
In: Pharmaceutical Research, Vol. 33, No. 11, 2016, p. 2630–2643.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Population pharmacokinetic modelling of morphine, gabapentin and their combination in the rat
AU - Papathanasiou, Theodoros
AU - Juul, Rasmus Vestergaard
AU - Gabel-Jensen, Charlotte
AU - Kreilgaard, Mads
AU - Lund, Trine Meldgaard
PY - 2016
Y1 - 2016
N2 - PurposeThe combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co-administration of the two drugs leads to modifications of their pharmacokinetic profiles.MethodsThe pharmacokinetics of morphine, morphine-3-glucuronide and gabapentin were characterised in rats following subcutaneous injections of morphine, gabapentin or their combination. Non-linear mixed effects modelling was applied to describe the pharmacokinetics of the compounds and possible interactions.ResultsThe plasma-concentration-time profiles of morphine and gabapentin were best described using a three- and a one-compartment disposition model respectively. Dose dependencies were found for morphine absorption rate and gabapentin bioavailability. Enterohepatic circulation of morphine-3-glucuronide was modelled using an oscillatory model. The combination did not lead to pharmacokinetic interactions for morphine or gabapentin but resulted in an estimated ~33% diminished morphine-3-glucuronide formation.ConclusionsThe finding of a lack of pharmacokinetic interaction strengthens the notion that the combination of the two drugs leads to better efficacy in pain treatment due to interaction at the pharmacodynamic level. The interaction found between gabapentin and morphine-3-glucuronide, the latter being inactive, might not have any clinical relevance.
AB - PurposeThe combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co-administration of the two drugs leads to modifications of their pharmacokinetic profiles.MethodsThe pharmacokinetics of morphine, morphine-3-glucuronide and gabapentin were characterised in rats following subcutaneous injections of morphine, gabapentin or their combination. Non-linear mixed effects modelling was applied to describe the pharmacokinetics of the compounds and possible interactions.ResultsThe plasma-concentration-time profiles of morphine and gabapentin were best described using a three- and a one-compartment disposition model respectively. Dose dependencies were found for morphine absorption rate and gabapentin bioavailability. Enterohepatic circulation of morphine-3-glucuronide was modelled using an oscillatory model. The combination did not lead to pharmacokinetic interactions for morphine or gabapentin but resulted in an estimated ~33% diminished morphine-3-glucuronide formation.ConclusionsThe finding of a lack of pharmacokinetic interaction strengthens the notion that the combination of the two drugs leads to better efficacy in pain treatment due to interaction at the pharmacodynamic level. The interaction found between gabapentin and morphine-3-glucuronide, the latter being inactive, might not have any clinical relevance.
U2 - 10.1007/s11095-016-1988-z
DO - 10.1007/s11095-016-1988-z
M3 - Journal article
C2 - 27380190
VL - 33
SP - 2630
EP - 2643
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 11
ER -
ID: 162934380