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A Pharmacokinetic-Pharmacodynamic Model of Morphine Exposure and Subsequent Morphine Consumption in Postoperative Pain
Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
Aalborg Univ Hosp, Orthopaed Surg Res Unit, Aalborg, Denmark.;Aalborg Univ Hosp, Dept Clin Med, Aalborg, Denmark..
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2016 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 33, no 5, 1093-1103 p.Article in journal (Refereed) PublishedText
Abstract [en]

To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Dose, formulation and time of morphine administration was available from a published study in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled release morphine was more effective than intravenous and oral immediate release formulations at equivalent average concentrations. Maximum effect was obtained for 8 h by oral controlled release doses a parts per thousand yenaEuro parts per thousand 15 mg, where probability of requesting a new dose was reduced to 20% for a typical patient. This study demonstrates the first quantitative link between exposure of morphine and subsequent morphine consumption and introduces an efficient visual predictive check approach with simulation of adaptive dosing.

Place, publisher, year, edition, pages
2016. Vol. 33, no 5, 1093-1103 p.
Keyword [en]
non-linear mixed effects modeling, opioid consumption, pharmacokinetics-pharmacodynamics, postoperative pain, repeated time to event
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-300301DOI: 10.1007/s11095-015-1853-5ISI: 000373629000004PubMedID: 26753622OAI: oai:DiVA.org:uu-300301DiVA: diva2:951306
Available from: 2016-08-08 Created: 2016-08-08 Last updated: 2016-08-08Bibliographically approved

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Nyberg, JoakimSimonsson, Ulrika S. H.
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