Theodoros Papathanasiou, Rasmus Vestergaard Juul, Charlotte Gabel-Jensen, Anne-Marie Heegaard, Mads Kreilgaard and Trine Meldgaard Lund
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen
Objectives: Combination of morphine and gabapentin has shown to be promising for managing postoperative pain [1]. Finding the right combination however has proven to be a challenge. PKPD modelling can be used to identify the optimal concentration-effect relationship of combinations.
Methods: In a blinded, randomized, 16 arms study, the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of morphine and gabapentin were evaluated. In the plantar incision model in the rat [2], a series of blood samples and hind paw withdrawal thresholds, after subcutaneous administration of morphine (1, 3 and 7 mg/kg), gabapentin (10, 30 and 100 mg/kg) or their combination (9 combinations of the above doses) were obtained. Population PKPD modelling was performed in NONMEM 7.3 [3].
Results: Morphine and gabapentin distribution were best described with a three- and a one- compartment model respectively. No significant PK interactions were identified. Synergistic effects in the PD level were characterized using a response surface approach. Full reversal of withdrawal thresholds for the pain stimulation was estimated at a morphine plasma concentration of 1600 ng/ml. Co-administration of up to ~40 µg/mL of gabapentin led to reduction of the needed morphine plasma concentration down to 1300 ng/ml (~ 21% reduction).
Conclusions: The synergistic effects of morphine and gabapentin were well described using a response surface approach. This study highlights the importance of finding the right combination in multimodal analgesia and the developed model might help in guiding clinical studies for the selection of appropriate doses.
References:
[1] Wu CL, Raja SN. Treatment of acute postoperative pain. Lancet [Internet]. Elsevier Ltd; 2011;377(9784):2215–25.
[2] Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain [Internet]. 1996 Mar;64(3):493–501.
[3] Beal S, Sheiner L, Boeckmann A, Bauer R. NONMEM user’s guides. (1989-2009). Icon Dev Solut Ellicott City, MD, USA, 2009.
Reference: PAGE 25 () Abstr 5987 [www.page-meeting.org/?abstract=5987]
Poster: Drug/Disease modeling - CNS