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Population Pharmacokinetic Modelling of Morphine, Gabapentin and their Combination in the Rat

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Abstract

Purpose

The 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.

Methods

The 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.

Results

The 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.

Conclusions

The 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.

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Abbreviations

EHC:

Enterohepatic circulation

M3G:

Morphine-3-Glucuronide

M6G:

Morphine-6-Glucuronide

MS/MS:

Tandem mass spectrometry

NONMEM:

Non-linear mixed effects modelling

OFV:

Objective function value

UPLC:

Ultra-high-performance liquid chromatography

VPC:

Visual predictive check

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Authors and Affiliations

  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Theodoros Papathanasiou, Rasmus Vestergaard Juul, Mads Kreilgaard & Trine Meldgaard Lund

  2. Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Charlotte Gabel-Jensen

Authors
  1. Theodoros Papathanasiou
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  2. Rasmus Vestergaard Juul
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  3. Charlotte Gabel-Jensen
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  4. Mads Kreilgaard
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  5. Trine Meldgaard Lund
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Correspondence to Trine Meldgaard Lund.

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Papathanasiou, T., Juul, R.V., Gabel-Jensen, C. et al. Population Pharmacokinetic Modelling of Morphine, Gabapentin and their Combination in the Rat. Pharm Res 33, 2630–2643 (2016). https://doi.org/10.1007/s11095-016-1988-z

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  • DOI: https://doi.org/10.1007/s11095-016-1988-z

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