• Rasmus Vestergaard Juul, Joakim Nyberg, Trine Meldgaard Lund, Sten Rasmussen, Mads Kreilgaard, Lona Louring Christrup, and Ulrika S H Simonsson.
• Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. rasmusvjuul@gmail.com.
• Pharm. Res. 2016 May 1; 33 (5): 1093-103.

PurposeTo characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation.MethodsDose, 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.ResultsThe 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 ≥ 15 mg, where probability of requesting a new dose was reduced to 20% for a typical patient.ConclusionThis 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.

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